Substituted piperidine spiro pyrrolidinone and piperidinone, preparation and therapeutic use thereof

ABSTRACT

The present disclosure relates to a series of substituted N-phenyl-bipyrrolidine carboxamides of formula (I). 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , m, n and p are as described herein. More specifically, the compounds of this invention are modulators of H3 receptors and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases modulated by H3 receptors including diseases associated with the central nervous system. Additionally, methods of preparation of substituted N-phenyl-bipyrrolidine carboxamides and intermediates therefor are disclosed.

This application is a continuation of International Application No.PCT/US2009/066673, filed Dec. 4, 2009, which claims the benefit ofpriority of U.S. Provisional Application No. 61/120,088, filed Dec. 5,2008, both of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a series of substituted piperidinespiro pyrrolidinone and piperidinone derivatives. The compounds of thisinvention are modulators of H3 receptors and are, therefore, useful aspharmaceutical agents, especially in the treatment and/or prevention ofa variety of diseases modulated by H3 receptors including diseasesassociated with the central nervous system. Additionally, this inventionalso relates to methods of preparation of substituted piperidine spiropyrrolidinone and piperidinone and intermediates therefor.

2. Description of the Art

Histamine is a ubiquitous messenger molecule released from mast cells,enterochromaffin-like cells, and neurons. The physiological actions ofhistamine are mediated by four pharmacologically defined receptors (H1,H2, H3 and H4). All histamine receptors exhibit seven transmembranedomains and are members of the G-protein-coupled receptor superfamily(GPCRs).

The H1 receptor was the first member of the histamine receptor family tobe pharmacologically defined, with the development of classicalantihistamines (antagonists), such as diphenhydramine and fexofenadine.While antagonism of the H1 receptor of the immune system is commonlyused for the treatment of allergic reactions, the H1 receptor is alsoexpressed in various peripheral tissues and the central nervous system(CNS). In the brain, H1 is involved in the control of wakefulness, mood,appetite and hormone secretion.

The H2 receptor is also expressed in the CNS, where it may modulateseveral processes, including cognition. However, H2 receptor antagonistshave primarily been developed to ameliorate gastric ulcers by inhibitinghistamine-mediated gastric acid secretion by parietal cells. Classic H2antagonists include cimetidine, ranitidine, and famotidine.

It should further be noted that H4 receptor function remains poorlydefined, but may involve immune regulation and inflammatory processes.

On the other hand, H3 receptors have also been pharmacologicallyidentified in the CNS, heart, lung, and stomach. The H3 receptor differssignificantly from other histamine receptors, exhibiting low sequencehomology (H1: 22%, H2: 21%, H4: 35%). H3 is a presynaptic autoreceptoron histamine neurons in the brain and a presynaptic heteroreceptor innonhistamine-containing neurons in both the central and peripheralnervous systems. In addition to histamine, H3 also modulates the releaseand/or synthesis of other neurotransmitters, including acetylcholine,dopamine, norepinepherin and serotonin. Of particular note, presynapticmodulation of histamine release by H3 allows significant regulation ofH1 and H2 receptors in the brain. Modulating multiple neurotransmittersignaling pathways, H3 may contribute to varied physiological processes.Indeed, extensive preclinical evidence indicates that H3 plays a role incognition, sleep-wake cycle and energy homeostasis.

Modulators of H3 function may be useful in the treatment of obesity andcentral nervous system disorders (Schizophrenia, Alzheimer's disease,attention-deficit hyperactivity disorder, Parkinson's disease,depression, and epilepsy), sleep disorders (narcolepsy and insomnia),cardiovascular disorders (acute myocardial infarction), respiratorydisorders (asthma), and gastrointestinal disorders. See generally,Hancock. Biochem. Pharmacol. 2006 Apr. 14; 71(8):1103-13 and Esbenshadeet al. Mol Interv. 2006 April; 6(2):77-88, 59.

U.S. Pat. No. 7,223,788 discloses a series of compounds, includingsubstituted bis-pyrrolidines, having melanin concentrating hormone (MCH)receptor antagonists. But the compounds disclosed therein are notreported to be active at the H3 receptor site.

All of the references described herein are incorporated herein byreference in their entirety.

Accordingly, it is an object of this invention to provide a series ofsubstituted piperidine spiro pyrrolidinone and piperidinone as selectiveH3 receptor ligands for treatment of H3 receptor regulated CNSdisorders.

It is also an object of this invention to provide processes for thepreparation of the substituted piperidine spiro pyrrolidinone andpiperidinone as disclosed herein.

Other objects and further scope of the applicability of the presentinvention will become apparent from the detailed description thatfollows.

SUMMARY OF THE INVENTION

It has now been found that the compounds of formula (I) are useful as H3receptor antagonists and/or inverse agonists. Thus in accordance withthe practice of this invention there is provided a compound of formula(I):

wherein

-   m is 1 or 2;-   n is 1 or 2;-   p is 1 or 2;-   R₁ is hydrogen, (C₁-C₆)alkyl, CF₃, (C₁-C₆)alkoxy-(C₁-C₆)alkyl; and-   R₂ is hydrogen, halogen, (C₁-C₆)alkyl or CF₃;-   R₃ is hydrogen, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl,    tert-butyloxycarbonyl, (C₃-C₇)cycloalkyl(C₁-C₆)alkyl, substituted or    unsubstituted tetrahydropyranyl, substituted or unsubstituted    tetrahydropyranylmethyl, substituted or unsubstituted furanylmethyl,    substituted or unsubstituted benzyl, (C₁-C₆)alkoxymethyl carbonyl,    substituted or unsubstituted (C₃-C₇)cycloalkane carbonyl,    substituted or unsubstituted benzoyl, substituted or unsubstituted    benzyl carbonyl, substituted or unsubstituted naphthyl carbonyl,    substituted or unsubstituted pyridine carbonyl, substituted or    unsubstituted furan carbonyl, substituted or unsubstituted    tetrahydropyran carbonyl, substituted or unsubstituted benzene    sulfonyl, wherein the substituents are selected from halogen,    trifluoromethoxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl or CF₃,    benzyloxycarbonyl.

This invention further includes various salts of the compounds offormula (I) including various enantiomers or diastereomers of compoundsof formula (I).

In other aspects of this invention there are also provided variouspharmaceutical compositions comprising one or more compounds of formula(I) as well as their therapeutic use in alleviating various diseaseswhich are mediated in-part and/or fully by H3 receptors.

DETAILED DESCRIPTION OF THE INVENTION

The terms as used herein have the following meanings:

As used herein, the expression “(C₁-C₆)alkyl” includes methyl and ethylgroups, and straight-chained or branched propyl, and butyl groups.Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl andtert-butyl. Derived expressions such as “(C₁-C₆)alkoxy”,“(C₁-C₆)alkoxy(C₁-C₆)alkyl”, or “hydroxy(C₁-C₆)alkyl” are to beconstrued accordingly.

As used herein, the expression “cycloalkyl” includes all of the knowncyclic radicals. Representative examples of “cycloalkyl” include withoutany limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, and the like. Derived expressions such as“cycloalkoxy”, “cycloalkylalkyl”, “cycloalkylaryl”, “cycloalkylcarbonyl”are to be construed accordingly.

As used herein, the expression “(C₁-C₆)perfluoroalkyl” means that all ofthe hydrogen atoms in said alkyl group are replaced with fluorine atoms.Illustrative examples include trifluoromethyl and pentafluoroethyl, andstraight-chained or branched heptafluoropropyl, nonafluorobutyl,undecafluoropentyl and tridecafluorohexyl groups. Derived expression,“(C₁-C₆)perfluoroalkoxy”, is to be construed accordingly.

As used herein, the expression “(C₆-C₁₀)aryl” means substituted orunsubstituted phenyl or naphthyl. Specific examples of substitutedphenyl or naphthyl include o-, p-, m-tolyl, 1,2-, 1,3-, 1,4-xylyl,1-methylnaphthyl, 2-methylnaphthyl, etc. “Substituted phenyl” or“substituted naphthyl” also include any of the possible substituents asfurther defined herein or one known in the art. Derived expression,“(C₆-C₁₀)arylsulfonyl,” is to be construed accordingly.

As used herein, the expression “(C₆-C₁₀)aryl(C₁-C₄)alkyl” means that the(C₆-C₁₀)aryl as defined herein is further attached to (C₁-C₄)alkyl asdefined herein. Representative examples include benzyl, phenylethyl,2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl and the like.Similarly, the expression “(C₆-C₁₀)arylcarbonyl” shall be construedaccordingly. Representative examples include benzoyl, naphthylcarbonyl,and the like.

As used herein, the expression “heteroaryl” includes all of the knownheteroatom containing aromatic radicals. Representative 5-memberedheteroaryl radicals include furanyl, thienyl or thiophenyl, pyrrolyl,isopyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl,and the like. Representative 6-membered heteroaryl radicals includepyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the likeradicals. Representative examples of bicyclic heteroaryl radicalsinclude, benzofuranyl, benzothiophenyl, indolyl, quinolinyl,isoquinolinyl, cinnolyl, benzimidazolyl, indazolyl, pyridofuranyl,pyridothienyl, and the like radicals. Derived expression“heteroarylcarbonyl” shall be construed accordingly, e.g.,pyridinecarbonyl, furancarbonyl, and the like.

As used herein, the expression “heterocycle” includes all of the knownreduced heteroatom containing cyclic radicals. Representative 5-memberedheterocycle radicals include tetrahydrofuranyl, tetrahydrothiophenyl,pyrrolidinyl, 2-thiazolinyl, tetrahydrothiazolyl, tetrahydrooxazolyl,and the like. Representative 6-membered heterocycle radicals includepiperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,tetrahydropyranyl, and the like. Various other heterocycle radicalsinclude, without any limitation, aziridinyl, azepanyl, diazepanyl,diazabicyclo[2.2.1]hept-2-yl, and triazocanyl, and the like. Derivedexpression “heterocyclecarbonyl” and “heterocycloalkyl(C₁-C₆)alkyl”shall be construed accordingly.

“Halogen” or “halo” means chloro, fluoro, bromo, and iodo.

As used herein, “patient” means a warm blooded animal, such as forexample rat, mice, dogs, cats, guinea pigs, and primates such as humans.

As used herein, the expression “pharmaceutically acceptable carrier”means a non-toxic solvent, dispersant, excipient, adjuvant, or othermaterial which is mixed with the compound of the present invention inorder to permit the formation of a pharmaceutical composition, i.e., adosage form capable of administration to the patient. One example ofsuch a carrier is pharmaceutically acceptable oil typically used forparenteral administration.

The term “pharmaceutically acceptable salts” as used herein means thatthe salts of the compounds of the present invention can be used inmedicinal preparations. Other salts may, however, be useful in thepreparation of the compounds according to the invention or of theirpharmaceutically acceptable salts. Suitable pharmaceutically acceptablesalts of the compounds of this invention include acid addition saltswhich may, for example, be formed by mixing a solution of the compoundaccording to the invention with a solution of a pharmaceuticallyacceptable acid such as hydrochloric acid, hydrobromic acid, nitricacid, sulfamic acid, sulfuric acid, methanesulfonic acid,2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, fumaric acid,maleic acid, hydroxymaleic acid, malic acid, ascorbic acid, succinicacid, glutaric acid, acetic acid, propionic acid, salicylic acid,cinnamic acid, 2-phenoxybenzoic acid, hydroxybenzoic acid, phenylaceticacid, benzoic acid, oxalic acid, citric acid, tartaric acid, glycolicacid, lactic acid, pyruvic acid, malonic acid, carbonic acid orphosphoric acid. The acid metal salts such as sodium monohydrogenorthophosphate and potassium hydrogen sulfate can also be formed. Also,the salts so formed may present either as mono- or di-acid salts and canexist substantially anhydrous or can be hydrated. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include alkali metalsalts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g.calcium or magnesium salts, and salts formed with suitable organicligands, e.g. quaternary ammonium salts. The expression “stereoisomers”is a general term used for all isomers of the individual molecules thatdiffer only in the orientation of their atoms in space. Typically itincludes mirror image isomers that are usually formed due to at leastone asymmetric center, (enantiomers). Where the compounds according tothe invention possess two or more asymmetric centers, they mayadditionally exist as diastereoisomers, also certain individualmolecules may exist as geometric isomers (cis/trans). Similarly, certaincompounds of this invention may exist in a mixture of two or morestructurally distinct forms that are in rapid equilibrium, commonlyknown as tautomers. Representative examples of tautomers includeketo-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers,imine-enamine tautomers, etc. It is to be understood that all suchisomers and mixtures thereof in any proportion are encompassed withinthe scope of the present invention.

As used herein, ‘R’ and ‘S’ are used as commonly used terms in organicchemistry to denote specific configuration of a chiral center. The term‘R’ (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term‘S’ (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon sequence rules wherein prioritizationis first based on atomic number (in order of decreasing atomic number).A listing and discussion of priorities is contained in Stereochemistryof Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N.Mander, editors, Wiley-Interscience, John Wiley & Sons, Inc., New York,1994.

In addition to the (R)-(S) system, the older D-L system may also be usedherein to denote absolute configuration, especially with reference toamino acids. In this system a Fischer projection formula is oriented sothat the number 1 carbon of the main chain is at the top. The prefix ‘D’is used to represent the absolute configuration of the isomer in whichthe functional (determining) group is on the right side of the carbon atthe chiral center and ‘L’, that of the isomer in which it is on theleft.

In a broad sense, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a few of the specificembodiments as disclosed herein, the term “substituted” meanssubstituted with one or more substituents independently selected fromthe group consisting of (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₁-C₆)perfluoroalkyl, phenyl, hydroxy, —CO₂H, an ester, an amide,(C_(r) C₆)alkoxy, (C₁-C₆)thioalkyl, (C₁-C₆)perfluoroalkoxy, —NH₂, Cl,Br, I, F, —NH-lower alkyl, and —N(lower alkyl)₂. However, any of theother suitable substituents known to one skilled in the art can also beused in these embodiments.

“Therapeutically effective amount” means an amount of the compound whichis effective in treating the named disease, disorder or condition.

The term “treating” refers to:

-   -   (i) preventing a disease, disorder or condition from occurring        in a patient that may be predisposed to the disease, disorder        and/or condition, but has not yet been diagnosed as having it;    -   (ii) inhibiting the disease, disorder or condition, i.e.,        arresting its development; and    -   (iii) relieving the disease, disorder or condition, i.e.,        causing regression of the disease, disorder and/or condition.

Thus, in accordance with the practice of this invention there isprovided a compound of the formula I: This invention further includesvarious salts of the compounds of formula (I) including variousenantiomers or diastereomers of compounds of formula (I).

In other aspects of this invention there are also provided variouspharmaceutical compositions comprising one or more compounds of formula(I) as well as their therapeutic use in alleviating various diseaseswhich are mediated in-part and/or fully by H3 receptors.

Thus, in accordance with the practice of this invention there isprovided a compound of the formula I:

wherein

-   m is 1 or 2;-   n is 1 or 2;-   p is 1 or 2;-   R₁ is hydrogen, (C₁-C₄)alkyl, CF₃, (C₁-C₄)alkoxy-(C₁-C₄)alkyl; and-   R₂ is hydrogen, halogen, (C₁-C₄)alkyl or CF₃;-   R₃ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkyloxycarbonyl, such as    tert-butyloxycarbonyl, (C₃-C₇)cycloalkyl(C₁-C₆)alkyl, substituted or    unsubstituted heterocycle, such as tetrahydropyranyl, substituted or    unsubstituted heterocycloalkyl(C₁-C₆)alkyl, such as    tetrahydropyranylmethyl, substituted or unsubstituted 5- or    6-membered ring heteroaryl(C₁-C₆)alkyl, such as furanylmethyl,    substituted or unsubstituted benzyl, (C₁-C₄)alkoxymethylcarbonyl,    substituted or unsubstituted (C₃-C₇)cycloalkanecarbonyl, substituted    or unsubstituted benzylcarbonyl, substituted or unsubstituted    (C₆-C₁₀)arylcarbonyl, such as naphthylcarbonyl, benzoyl, etc.,    substituted or unsubstituted 5 or 6-membered ring    heteroarylcarbonyl, such as pyridinecarbonyl or furancarbonyl,    substituted or unsubstituted heterocyclecarbonyl, such as    tetrahydropyrancarbonyl, substituted or unsubstituted    benzenesulfonyl, wherein the substituents are selected from halogen,    trifluoromethoxy, (C₁-C₄)alkoxy, (C₁-C₄)alkyl or CF₃.

This invention further includes various salts of the compounds offormula (I) including various enantiomers or diastereomers of compoundsof formula (I). As noted hereinabove and by way of specific exampleshereafter all of the salts that can be formed including pharmaceuticallyacceptable salts are part of this invention. As also noted hereinaboveand hereafter all of the conceivable enantiomeric and diastereomericforms of compounds of formula (I) are part of this invention.

In one of the embodiments, there is also provided the compounds offormula (I) wherein

-   n, p and m are 1;-   R₁ is methyl, ethyl, isopropyl, n-propyl or methoxymethyl;-   R₂ is hydrogen, fluorine, chlorine, methyl, ethyl or CF₃; and-   R₃ is hydrogen, methoxymethylcarbonyl, tert-butyloxycarbonyl,    cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl,    tetrahydropyranyl, benzyl, furanylmethyl, cyclopentane-carbonyl,    cyclohexanecarbonyl, trifluoromethoxybenzoyl, fluorobenzoyl,    benzyl-carbonyl, naphthylcarbonyl, benzenesulfonyl, fluorobenzene    sulfonyl or methoxybenzenesulfonyl.

In another embodiment of this invention there is also provided acompound of formula (I), wherein n is 2 and m is 1; or n is 1 and m is2; p is 1 or 2;

-   R₁ is methyl or ethyl;-   R₂ is hydrogen, fluorine, chlorine, methyl, ethyl or CF₃; and-   R₃ is hydrogen, isopropyl, tert-butyloxycarbonyl, cyclopropylmethyl,    cyclopentylmethyl, cyclohexylmethyl, tetrahydropyranyl, benzyl,    furanylmethyl, tetrahydropyranylmethyl, cyclopentanecarbonyl,    cyclohexanecarbonyl, tetrahydropyrancarbonyl, benzoyl,    trifluoromethoxybenzoyl, fluorobenzoyl, benzyl-carbonyl,    naphthylcarbonyl, pyridinecarbonyl, furancarbonyl or    benzenesulfonyl.

In a further aspect of this invention the following compoundsencompassed by the scope of this invention without any limitation may beenumerated:

-   2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic    acid tert-butyl ester;-   2-[2-methyl-4-((2R,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic    acid tert-butyl ester;-   2-[2-methyl-4-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic    acid tert-butyl ester;-   2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic    acid tert-butyl ester;-   2-[2-methyl-4-((2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic    acid tert-butyl ester-   2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylic    acid tert-butyl ester;-   2-{4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl}-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylic    acid tert-butyl ester;-   4-{[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-methyl-carbamoyl}-4-propyl-piperidine-1-carboxylic    acid tert-butyl ester;-   2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic    acid tert-butyl ester;-   2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-trifluoromethyl-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic    acid tert-butyl ester;-   2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-fluoro-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic    acid tert-butyl ester;-   2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic    acid tert-butyl ester;-   2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic    acid tert-butyl ester;-   2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-fluoro-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic    acid tert-butyl ester;-   2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   8-cyclopentylmethyl-2-[2-methyl-4-(2-methyl-[1,3]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;-   8-benzenesulfonyl-2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;-   8-(4-methoxy-benzenesulfonyl)-2-[4-((2S,3′S)-2-methyl-[1,3′]-bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one-   2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   2-[2-methyl-4-((2R,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one    Hydrochloride;-   2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one    Hydrochloride;-   2-[2-methyl-4-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one    Hydrochloride;-   8-cyclopentylmethyl-2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   8-cyclopentylmethyl-2-[2-methyl-4-((2R,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   8-cyclopentylmethyl-2-[2-methyl-4-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   8-cyclopentylmethyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;-   2-[2-methyl-4-((2R,3′R)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;-   2-[2-methyl-4-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;-   2-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;-   3-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   3-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   3-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   3-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-9-(pyridine-4-carbonyl)-2,9-diaza-spiro[5.5]undecan-1-one;-   9-(furan-3-carbonyl)-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   9-benzoyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   9-(4-fluoro-benzoyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   9-cyclohexanecarbonyl-2-[2-fluoro-4-((2S,3′TS)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   2-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-9-(tetrahydro-pyran-4-carbonyl)-2,9-diaza-spiro[5.5]undecan-1-one;-   9-isopropyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   9-cyclohexylmethyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   9-cyclopropylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-9-(tetrahydro-pyran-4-yl)-2,9-diaza-spiro[5.5]undecan-1-one;-   9-benzyl-2-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   2-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-9-furan-2-ylmethyl-2,9-diaza-spiro[5.5]undecan-1-one;-   2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;-   2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;-   2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-fluoro-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;-   2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;-   2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;-   2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-fluoro-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;-   8-(4-fluoro-benzoyl)-2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl]-piperidin-1-yl)-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;-   8-cyclohexanecarbonyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;-   8-(4-fluoro-benzenesulfonyl)-2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;-   2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-8-(tetrahydro-pyran-4-carbonyl)-2,8-diaza-spiro[4.5]decan-1-one;-   8-cyclopentanecarbonyl-2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;-   8-cyclopropylmethyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;-   8-cyclopentylmethyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;-   8-cyclohexylmethyl-2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;-   2-{2-fluoro-4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-8-(tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one;-   2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1-yl)-2-trifluoromethyl-phenyl]-8-phenylacetyl-2,8-diaza-spiro[4.5]decan-1-one;-   8-(2-methoxy-acetyl)-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-8-(naphthalene-2-carbonyl)-2,8-diaza-spiro[4.5]decan-1-one;-   8-benzoyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   8-(furan-3-carbonyl)-2-[4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   8-furan-2-ylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   8-cyclopropylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-8-(tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one;    and-   2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one.

All of the above compounds may also include corresponding salts whereverpossible including the pharmaceutically acceptable salts thereof.

In another aspect of this invention the following compounds encompassedby compound of formula (I) of this invention without any limitation maybe enumerated:

-   8-cyclopentylmethyl-2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   8-cyclopentylmethyl-2-[2-methyl-4-((2R,3′R)-2-methyl-[1,3]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   8-cyclopentylmethyl-2-[2-methyl-4-((2S,3′R)-2-methyl-[1,3]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   8-cyclopentylmethyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;-   2-[2-methyl-4-((2R,3′R)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;-   2-[2-methyl-4-((2S,3′R)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;-   2-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;-   3-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   3-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   3-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   9-isopropyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   9-cyclohexylmethyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   9-cyclopropylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-9-(tetrahydro-pyran-4-yl)-2,9-diaza-spiro[5.5]undecan-1-one;-   9-benzyl-2-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;-   2-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-9-furan-2-ylmethyl-2,9-diaza-spiro[5.5]undecan-1-one;-   8-cyclopropylmethyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;-   8-cyclopentylmethyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;-   2-{2-fluoro-4-[3-((2S,3′S)-2-methyl-piperidin-1-yl]-pyrrolidin-1′-yl)-phenyl}-8-(tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one;-   8-furan-2-ylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;-   8-cyclopropylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;    and-   2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-8-(tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one;

Again all of the conceivable salts of the above noted compoundsincluding the pharmaceutically acceptable salts are part of thisinvention.

In another aspect of this invention the compound of this invention maybe represented by a specific stereoisomeric form of formula (II):

Wherein R₁, R₂, R₃, m, n and p are as defined hereinabove.

The compounds of this invention can be synthesized by any of theprocedures known to one skilled in the art. Specifically, several of thestarting materials used in the preparation of the compounds of thisinvention are known or are themselves commercially available. Thecompounds of this invention and several of the precursor compounds mayalso be prepared by methods used to prepare similar compounds asreported in the literature and as further described herein. Forinstance, see R. C. Larock, “Comprehensive Organic Transformations,” VCHpublishers, 1989.

It is also well known that in various organic reactions it may benecessary to protect reactive functional groups, such as for example,amino groups, to avoid their unwanted participation in the reactions.Conventional protecting groups may be used in accordance with standardpractice and known to one of skilled in the art, for example, see T. W.Greene and P. G. M. Wuts in “Protective Groups in Organic Chemistry”John Wiley and Sons, Inc., 1991. For example, suitable amine protectinggroups include without any limitation sulfonyl (e.g., tosyl), acyl(e.g., benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g.,benzyl), which may be removed subsequently by hydrolysis orhydrogenation as appropriate. Other suitable amine protecting groupsinclude trifluoroacetyl [—C(═O)CF₃] which may be removed by basecatalyzed hydrolysis, or a solid phase resin bound benzyl group, such asa Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker) or a2,6-dimethoxy-4-[2-(polystyrylmethoxy)ethoxy]benzyl, which may beremoved by acid catalyzed hydrolysis, for example with TFA.

More specifically, the compounds disclosed herein and various precursorsused therefor can be synthesized according to the following proceduresof Schemes 1-5, wherein R₁, R₂, R₃, m and n are as defined for Formula Iunless otherwise indicated.

For instance, Scheme 1 illustrates the preparation of the intermediate[1, 3]-pyrrolidinyl-pyrrolidine of formula (4), wherein R is as definedherein. First, in step 1, Scheme 1, suitably protected (for exampletert-butyloxycarbonyl (boc)) pyrrolidinone of formula (1) is condensedwith a desired substituted pyrrolidine of formula (2) by any of theknown reductive amination procedures to form an intermediate of formula(3). For instance, such condensation reactions are generally carried outin the presence of reducing agents such as triacetoxyborohydride in aninert atmosphere, such as nitrogen atmosphere. The reaction can becarried out either at sub-ambient, ambient or super-ambient reactiontemperatures and pressures. Typically, such reactions are carried out atroom temperature at atmospheric pressure of nitrogen. The reactionmixture is then worked-up using procedures known to skilled in the artto isolate the intermediate of formula (3).

In step 2, Scheme 1, the intermediate (3) is then de-protected to formthe desired [1,3′]-pyrrolidinyl-pyrrolidine of formula (4). Suchdeprotection reactions are generally carried out under acidicconditions, for example, in the presence of hydrochloric acid atsub-ambient to ambient temperatures, for example in the temperaturerange of about −10° C. to room temperature. However, other suitablereaction temperatures can also be used depending upon the nature of theintermediate of formula (3).

Scheme 2 illustrates preparation of enantiomerically pure isomers of the[1,3′]pyrrolidinyl-pyrrolidine of formula (9), wherein R is as definedherein. In step 1, Scheme 2, suitably protected (for example boc)pyrrolidine or piperidine alcohol of formula (5) is treated withp-toluene sulfonyl chloride to form intermediate of formula (6). Thisreaction can be carried out using any of the procedures known to oneskilled in the art, such as for example carrying out the reaction in thepresence of a suitable base such as triethylamine and DMAP in a suitableorganic solvent, preferably an aprotic solvent such as dichloromethaneat sub-ambient or ambient temperature conditions.

In step 2, Scheme 2, the intermediate of formula (6) is condensed with adesired pyrrolidine or piperidine of formula (7). Again, suchcondensation reactions can be carried out using any of the proceduresknown to one skilled in the art in order to obtain the intermediate offormula (8). Typically, such condensation reactions are carried out inthe presence of a base such as potassium carbonate in the presence ofsolvents such as acetonitrile at ambient to super-ambient temperatureconditions.

In step 3, Scheme 2, the intermediate of formula (8) is then reactedwith an acid, such as hydrochloric acid in a suitable solvent, such asdioxane, to form the desired stereospecific isomer of intermediate offormula (9). It has now been found that the intermediates of formula (9)can be readily formed in accordance with the process of this inventionwith high enantiomeric purity, specific details of which are providedhereinbelow by way of various examples. In general, the enantiomericpurity can be determined by chiral HPLC.

Scheme 3 illustrates the preparation of the intermediate of formula(13). In step 1, Scheme 3, commercially availablepiperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester, offormula (10) is treated with suitable base, such as nBuLi in presence ofHMPA in THF, followed by alkenyl halides, to form intermediate offormula (12). This reaction can be carried out using any of theprocedures known to one skilled in the art, such as reported in theliterature (Nagumo, S.; Matoba A.; et al, Tetrahedron, 2002, 58(49),9871-9877; Stafford, J. A.; Heathcock, C. H. J. Org. Chem., 1990,55(20), 5433-5434). In step 2, Scheme 3, the alkene (12) is cleaved withOsO₄ and NaIO₄ in propanol and water to form aldehyde (13).

Scheme 4 illustrates the preparation of compounds of this invention. Thealdehyde of formula (13) is condensed with a desired commerciallyavailable bromide of formula (16) by any of the known reductiveamination procedures to form an intermediate of formula (17). Forinstance, such condensation reactions are generally carried out in thepresence of reducing agents such as triacetoxyborohydride in an inertatmosphere, such as nitrogen atmosphere. The reaction can be carried outeither at sub-ambient, ambient or super-ambient reaction temperaturesand pressures. Typically, such reactions are carried out at roomtemperature at atmospheric pressure of nitrogen. The reaction mixture isthen worked-up using procedures known to skilled in the art to isolatethe intermediate of formula (17). The cyclization is then initiated bycatalytic amount of base, such as potassium t-butoxide in aproticsolvents, such THF, to form compounds of formula (18). The intermediateof formula (18) is then condensed with the amine intermediate (4) or (9)prepared according to Scheme 1 and 2 to form the compounds of thisinvention (19).

Scheme 5 illustrates further derivatization from the compound of formula(19). Removal of the protection group yields the amine (20). This aminecan be alkylated under reductive amination conditions or acylated withcarboxylic or sulfonic acid or its acid chloride or acid anhydride toform amides or sulfonamides.

As already noted hereinabove, the compounds of this invention canreadily be converted into salts. More particularly, the compounds of thepresent invention are basic, and as such compounds of this invention areuseful in the form of the free base or in the form of a pharmaceuticallyacceptable acid addition salt thereof. Acid addition salts may be a moreconvenient form for use; and, in practice, use of the salt forminherently amounts to use of the free base form. The acids which can beused to prepare the acid addition salts include preferably those whichproduce, when combined with the free base, pharmaceutically acceptablesalts, that is, salts whose anions are non-toxic to the patient inpharmaceutical doses of the salts, so that the beneficial inhibitoryeffects inherent in the free base are not vitiated by side effectsascribable to the anions. Although pharmaceutically acceptable salts ofsaid basic compound is preferred, all acid addition salts are useful assources of the free base form even if the particular salt, per se, isdesired only as an intermediate product as, for example, when the saltis formed only for purposes of purification, and identification, or whenit is used as intermediate in preparing a pharmaceutically acceptablesalt by ion exchange procedures.

In another aspect of this embodiment, a specific disease, a disorder ora condition that can be prevented and/or treated with the compound ofthis invention include, without any limitation the following:sleep-related disorders (specific examples include without anylimitation narcolepsy, attentional deficits, circadian rhythm sleepdisorders, obstructive sleep apnea, periodic limb movement and restlessleg syndrome, excessive sleepiness and drowsiness due to medicationside-effect, etc.), neurological disorders (specific examples that maybe enumerated include but not limited to dementia, Alzheimer's disease,multiple sclerosis, epilepsy and neuropathic pain), neuropsychologicaland cognitive disorders (a few of the specific examples include withoutany limitation include schizophrenia, attention deficit/hyperactivitydisorder, Alzheimer's disease, depression, seasonal affective disorder,and cognitive impairment). Certain of the disorders also includecognitive impairment associated with schizophrenia (CIAS), anxietydisorders such as generalized anxiety, panic disorder and post-traumaticstress disorder, and major depressive disorder. Other disorders includedementia of Alzheimer type (DAT), cognitive deficits related toneurological diseases such as Alzheimer, Parkinson, Huntington, agerelated cognitive impairment, mild cognitive impairment, vasculardementia, Lewis Body dementia and any other cognition associated tocognitive deficits.

As described hereinbelow by way of specific examples, the compounds offormula (I) bind to the H3 receptors and demonstrate inverse agonismversus H3 functional activity. Therefore, the compounds of thisinvention may have utility in the treatment of diseases or conditionsameliorated with H3 receptor ligands. More specifically, the compoundsof the present invention are H3 receptor ligands that modulate functionof the H3 receptor by antagonizing the activity of the receptor.Further, the compounds of this invention may be inverse agonists thatinhibit the basal activity of the receptor or they may be antagoniststhat completely block the action of receptor-activating agonists.Additionally, the compounds of this invention may also be partialagonists that partially block or partially activate the H3 receptor orthey may be agonists that activate the receptor. Thus the compounds ofthis invention may act differentially as antagonists, inverse agonistsand/or partial agonists depending on functional output, histamine toneand or tissue context. Accordingly, the differential activities of thesecompounds may allow for utility to ameliorate multiple disease states asspecifically enumerated above.

Thus in one aspect of this invention there is provided a method oftreating a disease in a patient, said disease selected from the groupconsisting of sleep related disorder, dementia, Alzheimer's disease,multiple sclerosis, cognitive disorder, attention deficit hyperactivitydisorder and depression, comprising administering to said patient atherapeutically effective amount of a compound of formula (I).

One of skill in the art readily appreciates that the pathologies anddisease states expressly stated herein are not intended to be limitingrather to illustrate the efficacy of the compounds of the presentinvention. Thus it is to be understood that the compounds of thisinvention may be used to treat any disease caused by the effects of H3receptors. That is, as noted above, the compounds of the presentinvention are modulators of H3 receptors and may be effectivelyadministered to ameliorate any disease state which is mediated all or inpart by H3 receptors.

All of the various embodiments of the compounds of this invention asdisclosed herein can be used in the method of treating various diseasestates as described herein. As stated herein, the compounds used in themethod of this invention are capable of inhibiting the effects of H3receptor and thereby alleviating the effects and/or conditions causeddue to the activity of H3.

In another embodiment of the method of this invention, the compounds ofthis invention can be administered by any of the methods known in theart. Specifically, the compounds of this invention can be administeredby oral, intramuscular, subcutaneous, rectal, intratracheal, intranasal,intraperitoneal or topical route.

Finally, in yet another embodiment of this invention, there is alsoprovided a pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of formula (I), including enantiomers,stereoisomers, and tautomers of said compound and pharmaceuticallyacceptable salts, solvates or derivatives thereof, with said compoundhaving the general structure shown in formula I as described herein.

As described herein, the pharmaceutical compositions of this inventionfeature H3 inhibitory activity and thus are useful in treating anydisease, condition or a disorder caused due to the effects of H3 in apatient. Again, as described above, all of the preferred embodiments ofthe compounds of this invention as disclosed herein can be used inpreparing the pharmaceutical compositions as described herein.

Preferably the pharmaceutical compositions of this invention are in unitdosage forms such as tablets, pills, capsules, powders, granules,sterile parenteral solutions or suspensions, metered aerosol or liquidsprays, drops, ampoules, auto-injector devices or suppositories; fororal, parenteral, intranasal, sublingual or rectal administration, orfor administration by inhalation or insufflation. Alternatively, thecompositions may be presented in a form suitable for once-weekly oronce-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection. An erodible polymercontaining the active ingredient may be envisaged. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective unit dosage forms such as tablets, pills and capsules.This solid preformulation composition is then subdivided into unitdosage forms of the type described above containing from 0.1 to about500 mg of the active ingredient of the present invention. Flavored unitdosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50or 100 mg, of the active ingredient. The tablets or pills of the novelcomposition can be coated or otherwise compounded to provide a dosageform affording the advantage of prolonged action. For example, thetablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterials can be used for such enteric layers or coatings, suchmaterials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The pharmaceutical compositions of this invention can be administered byany of the methods known in the art. In general, the pharmaceuticalcompositions of this invention can be administered by oral,intramuscular, subcutaneous, rectal, intratracheal, intranasal,intraperitoneal or topical route. The preferred administrations of thepharmaceutical composition of this invention are by oral and intranasalroutes. Any of the known methods to administer pharmaceuticalcompositions by an oral or an intranasal route can be used to administerthe composition of this invention.

In the treatment of various disease states as described herein, asuitable dosage level is about 0.01 to 250 mg/kg per day, preferablyabout 0.05 to 100 mg/kg per day, and especially about 0.05 to 20 mg/kgper day. The compounds may be administered on a regimen of 1 to 4 timesper day.

This invention is further illustrated by the following examples whichare provided for illustration purposes and in no way limit the scope ofthe present invention.

Examples (General)

As used in the examples and preparations that follow, the terms usedtherein shall have the meanings indicated: “kg” refers to kilograms, “g”refers to grams, “mg” refers to milligrams, “μg” refers to micrograms,“pg” refers to picograms, “lb” refers to pounds, “oz” refers to ounces,“mol” refers to moles, “mmol” refers to millimoles, “μmole” refers tomicromoles, “nmole” refers to nanomoles, “L” refers to liters, “mL” or“ml” refers to milliliters, “μL” refers to microliters, “gal” refers togallons, “° C.” refers to degrees Celsius, “R_(f)” refers to retentionfactor, “mp” or “m.p.” refers to melting point, “dec” refers todecomposition, “bp” or “b.p.” refers to boiling point, “mm of Hg” refersto pressure in millimeters of mercury, “cm” refers to centimeters, “nm”refers to nanometers, “abs.” refers to absolute, “conc.” refers toconcentrated, “c” refers to concentration in g/mL, “DMSO” refers todimethyl sulfoxide, “DMF” refers to N,N-dimethylformamide, “CDI” refersto 1,1′-carbonyldiimidazole, “DCM” or “CH₂Cl₂” refers todichloromethane, “DCE” refers to 1,2-dichloroethane, “HCl” refers tohydrochloric acid, “EtOAc” refers to ethyl acetate, “PBS” refers toPhosphate Buffered Saline, “IBMX” refers to 3-isobutyl-1-methylxanthine,“PEG” refers to polyethylene glycol, “MeOH” refers to methanol, “MeNH₂”refers to methyl amine, “N₂” refers to nitrogen gas, “iPrOH” refers toisopropyl alcohol, “Et₂O” refers to ethyl ether, “LAH” refers to lithiumaluminum hydride, “heptane” refers to n-heptane, “HMBA-AM” resin refersto 4-hydroxymethylbenzoic acid amino methyl resin, “PdCl₂(dppf)₂” refersto 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride DCMcomplex, “HBTU” refers to2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate,“DIEA” refers to diisopropylethylamine, “CsF” refers to cesium fluoride,“MeI” refers to methyl iodide, “AcN,” “MeCN” or “CH₃CN” refers toacetonitrile, “TFA” refers to trifluoroacetic acid, “THF” refers totetrahydrofuran, “NMP” refers to 1-methyl-2-pyrrolidinone, “H₂O” refersto water, “BOC” refers to t-butyloxycarbonyl, “brine” refers to asaturated aqueous sodium chloride solution, “M” refers to molar, “mM”refers to millimolar, “μM” refers to micromolar, “nM” refers tonanomolar, “N” refers to normal, “TLC” refers to thin layerchromatography, “HPLC” refers to high performance liquid chromatography,“HRMS” refers to high resolution mass spectrum, “L.O.D.” refers to losson drying, “μCi” refers to microcuries, “i.p.” refers tointraperitoneally, “i.v.” refers to intravenously, anhyd=anhydrous;aq=aqueous; min=minute; hr=hour; d=day; sat.=saturated; s=singlet,d=doublet; t=triplet; q=quartet; m=multiplet; dd=doublet of doublets;br=broad; LC=liquid chromatograph; MS=mass spectrograph;ESI/MS=electrospray ionization/mass spectrograph; RT=retention time;M=molecular ion, “˜”=approximately.

Reactions generally are run under a nitrogen atmosphere. Solvents aredried over magnesium sulfate and are evaporated under vacuum on a rotaryevaporator. TLC analyses are performed with EM Science silica gel 60F254 plates with visualization by UV irradiation. Flash chromatographyis performed using Alltech prepacked silica gel cartridges. The ¹H NMRspectra are run at 300 MHz on a Gemini 300 or Varian Mercury 300spectrometer with an ASW 5 mm probe, and usually recorded at ambienttemperature in a deuterated solvent, such as D₂O, DMSO-D₆ or CDCl₃unless otherwise noted. Chemical shifts values ( ) are indicated inparts per million (ppm) with reference to tetramethylsilane (TMS) as theinternal standard.

High Pressure Liquid Chromatography-Mass Spectrometry (LCMS) experimentsto determine retention times (R_(T)) and associated mass ions areperformed using one of the following methods:

Mass Spectra (MS) are recorded using a Micromass mass spectrometer.Generally, the method used was positive electro-spray ionization,scanning mass m/z from 100 to 1000. Liquid chromatography was performedon a Hewlett Packard 1100 Series Binary Pump & Degasser; Auxiliarydetectors used were: Hewlett Packard 1100 Series UV detector,wavelength=220 nm and Sedere SEDEX 75 Evaporative Light Scattering (ELS)detector temperature=46° C., N₂ pressure=4 bar.

LCT: Grad (AcN+0.05% TFA):(H₂O+0.05% TFA)=5:95 (0 min) to 95:5 (2.5 min)to 95:5 (3 min). Column: YMC Jsphere 33×2 4 μM, 1 ml/min

MUX: Column: YMC Jsphere 33×2, 1 ml/min

Grad (AcN+0.05% TFA):(H2O+0.05% TFA)=5:95 (0 min) to 95:5 (3.4 min) to95:5 (4.4 min).

LCT2: YMC Jsphere 33×2 4 μM, (AcN+0.05% TFA):(H2O+0.05% TFA)=5:95 (0min) to 95:5 (3.4 min) to 95:5 (4.4 min)

QU: YMC Jsphere 33×2 1 ml/min, (AcN+0.08% formic acid):(H2O+0.1% formicacid)=5:95 (0 min) to 95:5 (2.5 min) to 95:5 (3.0 min)

The following examples describe the procedures used for the preparationof various starting materials employed in the preparation of thecompounds of this invention.

INTERMEDIATES Intermediate (i)2-Methyl-[1,3]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester

To a solution of N—BOC-3-pyrrolidinone (4.22 g, 22.9 mmol) and2-methylpyrroline (1.95 g, 22.9 mmol) (HCl salt was made by addition of22.9 mL of 1 M HCl in ether into the DCM solution of 2-methylpyrroline,then evaporated) in DCE (60 mL) was added powdered sodiumtriacetoxyborohydride slowly under N₂ at r.t. The yellowish milkysolution was stirred at r.t. overnight. LC/MS—m/z 255 and 199 (base andM-tBu).

The reaction was quenched with aq. NaHCO₃ solution (100 mL). The twolayers were separated, and the aqueous layer was extracted with DCM (20mL×2). The combined DCM extracts were washed with sodium bicarbonate (10mL), and brine (5 mL×2), dried (anhydrous potassium carbonate),filtered, and concentrated in vacuo. The crude product was purified on asilica gel column, eluted with DCM and 7.5% MeOH in DCM to get 5.50 g(yield: 94%) of the title compound as a liquid. MS: 255 (M+H⁺); TLC: 0.5(10% MeOH in DCM).

Intermediate (ii) 2-Methyl-[1,3]bipyrrolidinyl hydrochloride

2-Methyl-[1,3]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester (5.50g, 21.62 mmol) was treated with 20 mL of 4 M HCl in dioxane at 0° C. Thesolution was stirred under nitrogen at r.t. overnight. TLC (10% MeOH inDCM) did not detect the starting material. N₂ was passed through thesolution with stirring. The outlet was passed through KOH solution toabsorb HCl for 30 min. The solvent was removed by evaporation to drynessto get the title compound as a hygroscopic gummy material, 5.3 g(˜100%). This material was used without further purification insubsequent steps as illustrated below. LCMS: R_(T)=0.35 minutes, MS: 155(M+H).

¹H NMR (D₂O, 300 MHz): 4.30 (m), 3.85 (m), 3.76 (s), 3.5 (m), 3.46 (m),3.32 (m), 2.66 (m), 2.28 (m), 2.10 (m), 1.46 (bs).

Intermediate (iii)(R)-3-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butylester

To a 2 L round-bottom flask equipped with a mechanical stirring rod anda 250 ml addition funnel was added p-tosyl chloride (58 g, 305 mmol, 1.5eq) and 600 ml of anhydrous DCM. The solution was cooled with ice-waterbath. Et₃N (65 ml) and DMAP (2.65 g) were added. A solution of(R)-3-(−)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1.0 eq) in 200 mlof DCM was added slowly. The reaction mixture was allowed to stir atroom temperature over night. TLC showed completion of the reaction. Theproduct had an R_(f) value of 0.3 (TLC developed in DCM). The reactionwas cooled by ice-water bath. Polymer-supported trisamine (32 g) wasadded and stirred for 30 min. Trisamine bead was filtered and rinsedwith 300-400 mL of DCM. The organic solution was washed with 200 mL ofH₃PO₄ (1M) solution twice, followed by saturated NaHCO₃ solution (200mL), and brine (200 mL). The organic phase was dried over K₂CO₃. Afterconcentration, the crude product was purified by a 750 g silica gelcartridge (DCM to 5% MeOH in DCM) to afford the title compound as abeige oil (52 g, 75%).

MS: 363 (M+Na⁺); TLC (DCM) Rf=0.3.

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 7.80 (d, 9.0 Hz, 2H), 7.35 (d, 7.8 Hz,2H), 5.04 (bs, 1H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1.43 (s,9H).

Intermediate (iv) (S)-3-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester

A round bottomed flask was charged with 80 mL of anhydrous DCM. Thesolvent was evacuated and purged with nitrogen. To this solvent wasadded (3S)-1-BOC-3-pyrrolidinol (obtained from Astatech), (16.32 g, 33.8mmol), DMAP (0.4 g). The solution was cooled to an ice-water bath. Tothis cold solution was added a solution of p-toluene-sulfonyl chloride(9.67 g, 50.87 mmol, 1.5 equiv.) in 20 mL of DCM. The ice-water bath wasremoved and the solution was stirred under nitrogen overnight. TLC (5%MeOH in DCM for SM, 12 visualization; DCM for product, UV) showed thecompletion of the reaction. The reaction was quenched by addition ofpolymer-supported amine (4.5 g), stirred 30 min. 50 mL of DCM was addedand filtered. The filtration pad was washed with DCM. The organic waswashed with H₃PO₄ (1M, 2×50 mL), followed by NaHCO₃ (50 mL, brine (50mL), dried (K₂CO₃), filtered and concentrated to a liquid. This waspurified on a 110 g silica gel column on Analogix using 0-2% MeOH in DCMto obtain pure product, 8.82 g (77% yield).

TLC (DCM) Rf=0.3. LC: Rt=3.55 min, 100% pure based on total ion, MS: 363(M+Na); 342, 327, 286 (base).

¹H NMR (300 MHz, CDCl₃), δ (ppm): 7.81 (d, 8.7 Hz, 2H), 7.37 (d, 8.7 Hz,2H), 5.04 (bs, 1H), 3.45 (m, 4H), 2.46 (s, 3H), 1.44 (s, 9H).

Intermediate (v) (2S,3′S)-2-Methyl-[1,3]bipyrrolidinyl-1′-carboxylicacid tert-butyl ester

The tosylate (52 g, 0.15 mol, 1.0 eq), (2S)-2-methylpyrrolidine (25.2 g,0.3 mol, 2.0 eq), anhydrous CH₃CN (500 ml), and dry K₂CO₃ powder (50 g,36 mmol, 2.4 eq) were added to a 2 L round-bottom flask equipped with amechanical stirrer and a reflux condenser. The resulting suspension wasstirred at 75° C. for 20 h. The heating block was set at 88° C.

LC/MS showed a trivial amount of starting material at m/z 363. Thereaction mixture was concentrated in vacuo. The residue was partitionedbetween 200 mL of water and 400 mL of DCM. The aqueous layer was washedwith 50 mL of DCM twice. The organic extracts were combined and washedwith 150 mL of saturated NaHCO₃ solution, 150 mL of brine, and driedover K₂CO₃. The crude was purified by silica gel column, eluted with5-10% MeOH in DCM. The product still had weak UV absorption at 254 nmand 280 nm. A pale yellow oil was obtained. Yield: 24.5 g (64%).

LCMS: R_(T)=1.27 minutes, MS: 255 (M+H).

¹H NMR (300 MHz, CDCl₃), δ (ppm): 3.15 (m, 2H), 3.3 (m, 3H), 2.97 (m,1H), 2.71 (m, 1H), 2.47 (m, 1H), 1.98 (m, 2H), 1.96-1.67 (m, 4H), 1.46(s, 9H), 1.06 (d, 6.2 Hz, 3H).

Intermediate (vi) (2R,3′S)-2-Methyl-[1,3]bipyrrolidinyl-1′-carboxylicacid tert-butyl ester

The title compound was prepared in a manner substantially the same asintermediate (2R,3′S)-2-Methyl-[1,3]bipyrrolidinyl-1′-carboxylic acidtert-butyl ester by condensing3-(3R)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butylester with R-(−)-2-methylpiperindine (obtained from AdvancedAsymmetrics). LCMS: R_(T)=1.05 minutes, MS: 255 (M+H).

¹H NMR (300 MHz, CDCl₃), δ (ppm): 3.30 (m, 1H), 3.14 (bs, 2H), 2.91 (m,1H), 2.75 (m, 1H), 2.51 (m, 1H), 2.07-1.69 (m, 6H), 1.46 (s, 9H), 1.10(d, 6.0 Hz, 3H).

Intermediate (vii) (2S,3′R)-2-Methyl-[1,3]bipyrrolidinyl-1′-carboxylicacid tert-butyl ester

3-(3S)-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butylester (6.82 g, 19.97 mmol, 1 equiv.) and S-(+)-2-methyl-piperindine(obtained from Advanced Asymmetrics), (3.40 g, 40 mmol, 2 equiv.) weredissolved in anhydrous CH₃CN (65 mL). To this colorless solution wasadded powder K₂CO₃ (powder, 325 mess, 98+%, 6.10 g, 44.2 mmol, 2.2equiv.) at r.t. The suspension was heated with stirring under nitrogenover an oil bath maintained at 80° C. for 24 h. TLC (3% MeOH in DCM forSM, 7.5% MeOH in DCM for product) showed the SM was consumed almostcompletely. LC/MS showed very little amount of SM at m/z 363.

The suspension was concentrated to dryness. The residue was taken inwater (25 mL) and DCM (80 mL). The two layers were separated, and theaqueous layer was extracted with DCM (20 mL×2). The combined DCMextracts were washed with sodium bicarbonate (25 mL), and brine (25 mL),dried (anhydrous potassium carbonate), filtered, and concentrated invacuo. The crude product was purified on a silica gel column (70 g) onAnalogix, eluted with MeOH in DCM (0 to 7.5%) to obtain 4.08 g (80.3%)of the title compound as a gummy material. LCMS: R_(T)=1.14 minutes, MS:255 (M+H).

¹H NMR (300 MHz, CDCl₃), δ (ppm): 3.30 (m, 1H), 3.14 (bs, 2H), 2.91 (m,1H), 2.75 (m, 1H), 2.51 (m, 1H), 2.07-1.69 (m, 6H), 1.46 (s, 9H), 1.10(d, 6.0 Hz, 3H).

Intermediate (viii) (2R,3′R)-2-Methyl-[1,3]bipyrrolidinyl-1′-carboxylicacid tert-butyl ester

The title compound was prepared in a manner substantially the same asintermediate (2R,3′S)-2-Methyl-[1,3]bipyrrolidinyl-1′-carboxylic acidtert-butyl ester by condensing3-(3S)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butylester and R-(−)-2-methylpiperindine (obtained from AdvancedAsymmetrics). LCMS:

R_(T)=1.09 minutes, MS: 255 (M+H).

¹H NMR (300 MHz, CDCl₃), δ (ppm): 3.15 (m, 2H), 3.3 (m, 3H), 2.97 (m,1H), 2.71 (m, 1H), 2.47 (m, 1H), 1.98 (m, 2H), 1.96-1.67 (m, 4H), 1.46(s, 9H), 1.06 (d, 6.2 Hz, 3H).

Intermediate (ix) (2S,3′R)-2-Methyl-[1,3]bipyrrolidinyl dihydrochloride

2(2S)-Methyl-[1,3′(3′R)]bipyrrolidinyl-1′-carboxylic acid tert-butylester (7.91 g, 31.14 mmol) was treated with 28.8 mL of HCl in dioxane at0° C. The solution was stirred under nitrogen at r.t. overnight. BothTLC (10% MeOH in DCM) and LC/MS did not detect the starting material.The reaction was judged complete.

N₂ was passed through the solution with stirring. The outlet was passedthrough KOH solution to absorb HCl for 1 h. The solvent was removed byevaporation to dryness to get the title compound as a hygroscopic verythick gummy (2HCl salt, hydrated—Exact composition unknown), 8.07 g(˜100%). MS: 155 (M+H).

¹H NMR: (D₂O, 300 MHz), δ (ppm): 11.6 (bs, 1H), 9.1 (bs, 1H) 4.12 (m,1H) 3.5, (m, 2H), 3.3-3.1 (m, 3H), 2.4-2.1 (m, 4H), 2.4 (m, 2H), 1.6 (m,1H), 1.4 (d, 6.0 Hz, 3H).

Intermediate (x) (2S,3′S)-2-Methyl-[1,3]bipyrrolidinyl dihydrochloride

(2S,3′S)-2-Methyl-[1,3]bipyrrolidinyl-1′-carboxylic acid tert-butylester (24.5 g) was dissolved in 30 ml of dry 1,4-dioxane. HCl solution(85 ml, 4M in dioxane) was added at 0° C., and allowed to stir at roomtemperature. Brown gum appeared after about 20 minutes. After 4 h, thereaction was complete. N₂ was passed through the flask for 1 h withstirring. The outlet passed though KOH solution to absorb HCl. Thesolvent was removed by vacuum to afford 29 g of hygroscopic beige gum.

LCMS: R_(T)=0.37 minutes, MS: 155 (M+H).

¹H NMR: (D₂O, 300 MHz), δ (ppm): 11.6 (bs, 1H), 9.1 (bs, 1H) 4.12 (m,1H) 3.5, (m, 2H), 3.3-3.1 (m, 3H), 2.4-2.1 (m, 4H), 2.4 (m, 2H), 1.6 (m,1H), 1.4 (d, 6.0 Hz, 3H)

Intermediate (xi) (2R,3′S)-2-Methyl-[1,3]bipyrrolidinyl dihydrochloride

The title compound was prepared in a manner substantially the same asintermediate (2S,3′R)-2-Methyl-[1,3]bipyrrolidinyl dihydrochloride byacid hydrolysis of 2(2R)-methyl-[1,3′(3′S)]bipyrrolidinyl-1′-carboxylicacid tert-butyl ester.

MS: 155 (M+H).

¹H NMR: (D₂O, 300 MHz), δ (ppm): 11.6 (bs, 1H), 9.1 (bs, 1H) 4.12 (m,1H) 3.5, (m, 2H), 3.3-3.1 (m, 3H), 2.4-2.1 (m, 4H), 2.4 (m, 2H), 1.6 (m,1H), 1.4 (d, 6.0 Hz, 3H).

Intermediate (xii) (2R,3′R)-2-Methyl-[1,3]bipyrrolidinyl dihydrochloride

The title compound was prepared in a manner substantially the same asintermediate (2S,3′R)-2-Methyl-[1,3]bipyrrolidinyl dihydrochloride byacid hydrolysis of 2-(2R)-methyl-[1,3′(3′R)]bipyrrolidinyl-1′-carboxylicacid tert-butyl ester.

MS: 155 (M+H).

¹H NMR: (D₂O, 300 MHz), δ (ppm): 11.6 (bs, 1H), 9.1 (bs, 1H) 4.12 (m,1H) 3.5, (m, 2H), 3.3-3.1 (m, 3H), 2.4-2.1 (m, 4H), 2.4 (m, 2H), 1.6 (m,1H), 1.4 (d, 6.0 Hz, 3H)

Intermediate (xiii) 4-Allyl-piperidine-1,4-dicarboxylic acid1-tert-butyl ester 4-ethyl ester

In a 250-mL RBF was weighed 6.1 g (60 mmol) of diisopropylamine anddissolved in THF. This solution was cooled to −78° C. To this was added24 mL of 2.5 M (60 mmol) of butyllithium in hexane and stirred for 15min, warmed up to 0° C. for 20 min, re-cooled to −78° C. To this wasadded piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester(12.87 g, 50 mmol) in THF (10 mL). There was almost no color change.This was stirred at −78° C. for 45 min. Then, a mixture of 5 g of HMPAand 10.92 g of allyl iodide was added via cannula. The solution wasstill clear, very light in yellow. This mixture was stirred at −78° C.for 20 min, then, the dry ice bath was removed and the stirring wascontinued to allow the reaction mixture warm to r.t. over 40 min. Thereaction mixture was poured into ice (˜50 g), sat'd NH₄Cl aq. (50 mL)and ether (50 mL). The two layers were separated, the aqueous layer wasextracted with ether (3×50 mL). The combined organic layers were washedwith brine, dried (K₂CO₃), filtered, and concentrated in vacuo to obtain15 g (100%) of the title compound as a yellow liquid,

LC R_(T)=3.45 min, MS: 198, 242 (M-tBu).

NMR (300 MHz, CDCl3) δ: NMR (300 MHz, CDCl3): 5.68 (m, 1H); 5.07 (, bs,1H), 5.04 (d, 10.2 Hz, 1H), 4.17 (q, 7.2, 2H), 3.88 (broad d, 9 Hz, 2H),2.9 (broad t, 12.9 Hz, 2H), 2.27 (d, 7.8 Hz, 2H), 2.1 (broad d, 13.2Hz), 1.45 (s, 9H), 1.26 (t, 7.2 Hz, 3H).

Intermediate (xiv) 4-(2-Oxo-ethyl)-piperidine-1,4-dicarboxylic acid1-tert-butyl ester 4-ethyl ester

4-Allyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethylester (2.97 g, 10 mmol) was dissolved in iPrOH (50.0 mL) and H₂O (10.0mL). To this was added a aqueous solution of NaIO₄ (4.68 g, 21.8 mmol)in water (40.0 mL), followed by addition of OsO₄ (8.4 mg, crystals, inone portion) at rt. The solution was stirred at rt. After 30 min, milkycloudy formed. Stirring was continued overnight. TLC and LC/MS did notdetect the SM, but it is still very milky. The reaction mixture waspoured into ice water (20 mL) and EtOAc (30 mL). The two layers wereseparated and the aqueous layer was extracted with EtOAc (3×15 mL). Thecombined extracts were washed with brine, and concentrated to dryness toget a liquid. The liquid was subject a reduced distillation to removeisopropanol. The remaining liquid was purified on a 50-g silica gelcolumn, eluted with MeOH in DCM (0-5%). Note: the product is not UVactive. Anisaldehyde visualization was used. The product fractions werecollected and concentrated to yield 1.03 g (34% yield) of the titlecompound as a liquid.

LC/MS: R_(T)=2.84 min, MS: 300.

NMR (300 MHz, CDCl₃) δ: 9.73 (t, 1.8 Hz, 1H), 4.22 (q, 7.2 Hz, 2H), 3.69(m, 2H), 3.20 (m, 2H), 2.68 (m, 2H), 2.12 (m, 2H), 1.52 (m, 2H), 1.49(s, 9H), 1.27 (t, 7.2 Hz, 3H).

Intermediate (xv)4-[2-(4-Bromo-2-methyl-phenylamino)-ethyl]-piperidine-1,4-dicarboxylicacid 1-tert-butyl ester 4-ethyl ester

2-Methyl-4-bromo-aniline (0.637 g, 3.427 mmol) was dissolved in DCE (15mL); to this solution was transferred a solution of4-(2-oxo-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester4-ethyl ester (1.03 g, 3.425 mmol) in DCE (35 mL). The flask wassubmerged in a water bath at rt. To this clear solution was then addedacetic acid (0.647 g, 10.8 mmol, 3.1 equiv), followed by addition ofpowder NaBH(OAc)₃ (2.18 g, 10.3 mmol, 3 equiv.) under N₂ at r.t. Theyellowish milky suspension was stirred at r.t. overnight. LC/MS showedm/z 469/471 at t=4.930 min. along with small amount of aniline sm at2.103 (186/188). TLC (5% of MeOH in DCM) showed no SM. of aldehyde, butaniline. The reaction was diluted with DCM (20 mL), cooled to ice-waterbath, and quenched with 10 mL of 1N NH₄OH. The two layers wereseparated, and the aqueous layer was extracted with DCM (15 mL×3). Thecombined DCM extracts were washed with sodium bicarbonate (10 mL), andbrine (10 mL), dried (anhydrous potassium carbonate), filtered, andconcentrated. The product was purified on a 40 g-silica gel columneluted with 0-2% of MeOH in DCM to get 0.65 g (41%) of the titlecompound as an oil.

LC/MS R_(T)=3.96 min, MS: 469/471 (M+H⁺)

NMR (300 MHz, CDCl3) δ: 7.21-7.13 (m, 2H), 6.42 (d, 8.4 Hz, 1H), 4.15(q, 7.2 Hz, 2H), 3.88 (m, 3H), 3.13 (m, 2H), 2.93 (m, 2H), 2.16 (bd,2H), 2.26 (s, 3H), 1.88 (m, 2H), 1.46 (s, 9H), 1.43 (m, 2H), 1.42 (t,7.2 Hz, 3H).

Intermediate (xvi)4-[2-(4-Bromo-phenylamino)-ethyl]-piperidine-1,4-dicarboxylic acid1-tert-butyl ester 4-ethyl ester

This intermediate was synthesized in substantially the same way asdescribed above from 1.75 g of the desired aldehyde to get 1.45 g (54%yield) of the title product as a colorless liquid.

LC/MS: R_(T)=3.81 mins; MS: 455/457

Intermediate (xvii)4-[2-(4-Bromo-2-trifluoromethyl-phenylamino)-ethyl]-piperidine-1,4-dicarboxylicacid 1-tert-butyl ester 4-ethyl ester

This intermediate was synthesized in substantially the same way asdescribed above from 1.75 g of the desired aldehyde to get 2.03 g (66%yield) of the title product as a yellow liquid.

LC/MS: R_(T)=4.18 mins; MS: 523/525.

Intermediate (xviii)4-[2-(4-Bromo-2-fluoro-phenylamino)-ethyl]-piperidine-1,4-dicarboxylicacid 1-tert-butyl ester 4-ethyl ester

This intermediate was synthesized in substantially the same way asdescribed above from 1.75 g of the desired aldehyde to get 1.97 g (71%yield) of the title product as an amber liquid.

LC/MS: R_(T)=3.95 mins; MS: 473/475.

Intermediate (xix)2-(4-Bromo-2-methyl-phenyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester

To a clear solution of4-[2-(4-Bromo-2-methyl-phenylamino)-ethyl]-piperidine-1,4-dicarboxylicacid 1-tert-butyl ester 4-ethyl ester (3.42 mmol) in THF (40 mL) wasadded a solution of potassium t-butoxide (1M in THF) 1 mL (1 mmol, 0.3equiv.) at r.t. (water bath at rt). The clear solution turned a littlebit cloudy. After 30 min, TLC (5% MeOH in DCM) showed the reaction iscomplete (spot to spot), LC/MS detected the product peak of 423/425 (t3.267 min). The reaction was cooled in an ice-water bath, diluted with100 mL of DCM, quenched with 20 mL of water. The two layers wereseparated. The aqueous layer was extracted with DCM (2×20 mL). Thecombined DCM extracts were washed with brine, and concentrated onrotavap to yield 0.90 g (63% yield) of the title compound as a whitesolid.

LC R_(T)=4.00 min, MS: 423/425;

NMR (300 MHz, CDCl3) δ: 7.42 (m, 1H), 7.35 (m, 1H), 7.00 (d, 8.4 Hz,1H), 4.03 (m, 2H), 3.64 (t, 6.9 Hz, 2H), 3.06 (m, 2H), 2.17 (s, 3H),2.13 (m, 2H), 1.96 (m, 2H), 1.57 (m, 2H), 1.47 (s, 9H).

Intermediate (xx)2-(4-Bromo-phenyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acidtert-butyl ester

This intermediate is synthesized in the same way as described above from1.44 g of the desired aniline to get 0.955 g (74% yield) of the titleproduct as a beige solid.

LC/MS: 4.13 mins./409.09

Intermediate (xxi)2-(4-Bromo-2-trifluoromethyl-phenyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester

This intermediate is synthesized in the same way as described above from2.04 g of the desired aniline to get 1.79 g (97% yield) of the titleproduct as a yellow solid.

LC/MS: R_(T)=4.13 mins./MS: 477

Intermediate (xxii)2-(4-Bromo-2-fluoro-phenyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester

This intermediate is synthesized in the same way as described above from1.98 g of the desired aniline to get 1.75 g (98% yield) of the titleproduct as a brown solid.

LC/MS: R_(T)=3.98 mins. MS: 427

Intermediate (xxiii) 4-But-3-enyl-piperidine-1,4-dicarboxylic acid1-tert-butyl ester 4-ethyl ester

A mixture of THF (160 mL) and diisopropyl amine (9.92 mL, 70.8 mmol, 1.2eq) was cooled to −78° C. and a 2.5 M solution of n-BuLi in heptanes(28.3 mL, 70.8 mmol, 1.2 eq) was added slowly. The solution was stirredfor 15 min, warmed to 0° C. for 20 min and cooled back to −78° C. EthylN-Bocpiperidine-4-carboxylate (11 mL, 59 mmol, 1 eq.) in 10 mL of THFwas added drop-wise and stirred for 40 min before it was warmed to rt.The reaction mixture was stirred for 12 h, transferred to a separatoryfunnel, quenched with 500 mL of water and extracted with ethyl acetate(2×300 mL). The combined organics were dried over Na2SO4 andconcentrated under vacuum to give the title compound as a yellow oil(13.9 g, 76%).

LC/MS: R_(T)=4.15 mins. MS: 312

NMR (300 MHz, CDCl3) δ: 5.75 (ddt, 1H), 5.02 (d, 1H), 4.96 (t, 1H), 4.18(q, 2H), 3.89-3.86 (m, 2H), 2.88 (t, 2H), 2.11 (d, 2H), 1.99-1.93 (m,2H), 1.66-1.57 (m, 2H), 1.45 (s, 9H), 1.43-1.32 (m, 2H), 1.27 (t, 3H)

Intermediate (xxiv) 4-(3-Oxo-propyl)-piperidine-1,4-dicarboxylic acid1-tert-butyl ester 4-ethyl ester

4-But-3-enyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethylester (13.5 g, 43.48 mmol, 1 eq) was dissolved in i-PrOH (217 mL) and asolution of NaIO₄ (20.23 g, 94.6 mmol, 2.18 eq) in 217 mL of water wasadded followed by OsO₄ (37 mg, 0.144 mmol, 0.003 eq). The reactionmixture was vigorously stirred for 6 h. The reaction mixture was thenquenched with 1500 mL of water, transferred to a separatory funnel andextracted with ethyl acetate (3×200 mL). The combined organics weredried over Na2SO4 and purified by column chromatography on silica gel(300 g column, 30% EtOAc in heptanes; 50 mL/min). This gave 8.5 g (63%)of the title compound as a beige oil.

LC R_(T)=3.62 min, MS: 314;

NMR (300 MHz, CDCl3) δ: 9.75 (s, 1H), 4.17 (q, 2H), 4.16-4.14 (m, 2H),2.87 (t, 2H), 2.43 (dt, 2H), 2.10 (d, 2H), 1.85 (t, 2H), 1.45 (s, 9H),1.36 (dd, 2H), 1.27 (t, 3H).

Intermediate (xxv)4-[3-(4-Bromo-2-methyl-phenylamino)-propyl]-piperidine-1,4-dicarboxylicacid 1-tert-butyl ester 4-ethyl ester

2-Methyl-4-bromo-aniline (1.68 g, 9.05 mmol, 1 eq) was dissolved in1,2-dichloroethane (95 mL). A solution of4-(3-Oxo-propyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester4-ethyl ester (2.8 g, 9.05 mmol, 1 eq) in 95 mL of 1,2-dichloroethanewas added to the previous solution followed by glacial acetic anhydride(1.74 g, 28.05 mol, 3.1 eq) and NaBH(OAc)₃ (5.76 g, 27.15 mmol, 3 eq).The reaction mixture was stirred for 48 h, quenched with 200 mL ofwater, transferred to a separatory funnel and extracted withdichloromethane (2×100 mL). The combined organics were dried over Na2SO4and purified by column chromatography on silica gel (200 g column, 25%EtOAc in heptanes; 50 mL/min). This gave 3.78 g (86%) of the titlecompound as a beige gum.

LC R_(T)=4.82 min, MS: 383;

NMR (300 MHz, CDCl3) δ: 7.16 (dd, 1H), 7.15 (s, 1H), 6.40 (d, 1H), 4.16(q, 2H), 3.87 (d, 2H), 3.41 (s, 1H), 3.09-3.09 (m, 2H), 2.89 (t, 2H),2.13 (s, 1H), 2.09 (s, 3H), 1.66-1.52 (m, 3H), 1.45 (s, 9H), 1.26 (d,3H), 1.27-1.17 (m, 2H), 0.88 (t, 3H)

Intermediate (xxvi)4-[3-(4-Bromo-phenylamino)-propyl]-piperidine-1,4-dicarboxylic acid1-tert-butyl ester 4-ethyl ester

This intermediate was synthesized in substantially the same way asabove.

LC R_(T)=4.65 min, MS: 469 (M+H);

NMR (300 MHz, CDCl3) δ: 7.23 (d, 2H), 6.44 (d, 2H), 4.16 (q, 2H), 3.87(d, 2H), 3.61 (s, 1H), 3.04 (t, 2H0, 2.88 (t, 2H), 2.10 (d, 2H),1.63-1.48 (m, 3H), 1.45 (s, 9H), 1.26 (d, 3H), 0.88 (t, 3H)

Intermediate (xxvii)4-[3-(4-Bromo-2-fluoro-phenylamino)-propyl]-piperidine-1,4-dicarboxylicacid 1-tert-butyl ester 4-ethyl ester

This intermediate was synthesized in substantially the same way asabove.

LC R_(T)=4.82 min, MS: 487 (M+H);

NMR (300 MHz, CDCl3) δ: 7.16-7.03 (m, 2H), 6.65 (t, 1H), 4.16 (q, 2H),3.84-3.72 (m, 2H), 3.08 (q, 2H), 2.88 (t, 2H), 2.10 (d, 2H), 1.66-1.52(m, 3H), 1.45 (s, 9H), 1.40-1.34 (m, 1H), 1.26 (d, 3H), 0.88 (t, 3H).

Intermediate (xxviii)2-(4-Bromo-2-methyl-phenyl)-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylicacid tert-butyl ester

4-[3-(4-Bromo-2-methyl-phenylamino)-propyl]-piperidine-1,4-dicarboxylicacid 1-tert-butyl ester 4-ethyl ester (3.78 g, 7.81 mmol, 1 eq) wasdissolved in THF (80 mL). A 1M solution of NaOt-Bu in THF (7.8 mL, 7.8mmol, 1 eq) was added and the reaction mixture was stirred for 2 h atrt. The reaction mixture was stirred for 48 h, quenched with 250 mL ofwater, transferred to a separatory funnel and extracted withdichloromethane (2×150 mL). The combined organics were dried over Na₂SO₄and purified by column chromatography on silica gel (200 g column, 50%EtOAc in heptanes; 50 mL/min). This gave 2.49 g (73%) of the titlecompound as a beige gum.

LC R_(T)=4.08 min, MS: 437 (M+H);

NMR (300 MHz, CDCl3) δ: 7.40 (s, 1H), 7.35 (dd, 1H), 6.96 (d, 1H),3.85-3.71 (m, 2H), 3.60-3.54 (m, 1H), 3.39-3.22 (m, 3H), 2.21-2.04 (m,3H), 2.12 (s, 3H), 1.97-1.88 (m, 3H), 1.45 (s, 9H), 1.31-1.24 (m, 2H).

Intermediate (xxix)2-(4-Bromo-phenyl)-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylic acidtert-butyl ester

This intermediate was synthesized in substantially the same way asabove.

LC R_(T)=3.97 min, MS: 423 (M+H);

NMR (300 MHz, CDCl3) δ: 7.49 (d, 2H), 7.09 (d, 2H), 3.83-3.75 (m, 2H),3.64-3.60 (m, 2H), 3.31-3.22 (m, 2H), 2.18-2.04 (m, 2H), 1.98-1.90 (m,4H), 1.46 (s, 9H), 1.31-1.24 (m, 2H).

Intermediate (xxx)2-(4-Bromo-2-fluoro-phenyl)-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylicacid tert-butyl ester

This intermediate was synthesized in substantially the same way asabove.

LC R_(T)=4.05 min, MS: 441 (M+H);

NMR (300 MHz, CDCl3) δ: 7.33-7.28 (m, 2H), 7.09 (t, 1H), 3.80-3.72 (m,2H), 3.59-3.55 (m, 2H), 3.36-3.27 (m, 2H), 2.16-2.04 (m, 2H), 1.99-1.90(m, 4H), 1.46 (s, 9H), 1.31-1.24 (m, 2H)

Example 12-[2-Methyl-4-((2R,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester

The HCl salt of (2R,3′S)-2-Methyl-[1,3]bipyrrolidinyl was dissolved in 2mL of MeOH with the aid of sonication. To the solution was added 50 mLof DCM. The solution was cooled to an ice-water bath. To this solutionwas added powder KOH (0.5 g, 9.5 mmol, 2.6 equiv. to the amine salt)with stirring under N2. The stirring was continued for 1 h. 0.5 g ofpowder K₂CO₃ was added with stirring to form a nice suspension. Thesuspension was filtered through a Celite pad, rinsed with DCM until noamine was leach out by TLC (20% MeOH in DCM, anisaldehyde visualization,white spot just above the origin). The solution was concentrated todryness; the residue was further dried under high vacuum with stirringfor 1 h, re-dissolved in anhydrous toluene and ready to use.

An 20-mL vial containing a stir bar was charged with Pd₂(dba)₃ (0.01equiv., 0.002036 mmol, 2 mg.),2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-biphenyl (0.05 equiv.,0.01018 mmol, 5 mg.), and sodium t-butoxide (2.5 equiv., 0.509 mmol, 50mg.). The vial was de-gassed and refilled with N₂ three cycles. Asolution of2-(4-bromo-2-methyl-phenyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester (86 mg, 0.2 mmol; prepared from 0.82 g dissolvedin 9.5 mL of toluene, 1 mL was used for each reaction) was introducedand the red solution was stirred for 1 min at rt, then the amine intoluene (1.11 equiv., 1 mL each, corresponding to 60 mg, 0.22 mmol ofbipyrrolidine) was introduced. The flask was evacuated and backfilledwith N2. The reaction was heated in an oil bath set at 90° C. for 2.5 h,allowed to cool down to room temperature. Toluene was evaporated underreduced pressure. The residue was re-dissolved in DCM (10 mL) and aq.NaHCO₃ (2 mL). The two layers were separated and the aqueous layer wasextracted with DCM (3×5 mL). The combined DCM extracts were washed withsodium bicarbonate (5 mL), and brine (5 mL), dried (anhydrous potassiumcarbonate), filtered, and concentrated. The crude product was purifiedon a 10-g silica gel column eluted with DCM and 5% of 7N NH3 MeOH in DCMto obtain the title compound as a semi-solid.

LC, R_(T)=2.63 mins; MS: 497.

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 6.96 (m, 1H), 6.39 (m, 2H), 4.04 (m,2H), 3.59 (t, 6.6 Hz, 2H), 3.45-3.17 (m, 5H), 3.02 (m, 3H), 2.79 (m,1H), 2.54 (q, 6.0 Hz, 1H), 2.30-1.90 (m, 9H), 1.76 (m, 3H), 1.62-1.39(m, 12H), 1.14 (d, 6.3 Hz, 3H).

Example 22-[2-Methyl-4-((2R,3′R)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester

The title compound was prepared in a manner substantially the same asExample 1 to obtain the title compound as a semi-solid.

LC, R_(T)=2.66 mins; MS: 497.

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 6.96 (m, 1H), 6.39 (m, 2H), 4.04 (m,2H), 3.59 (t, 6.6 Hz, 2H), 3.50 (t, 7.2 Hz, 1H), 3.37 (dt, 2.2 Hz, 9.3Hz, 1H), 3.245 (m, 3H), 3.04 (m, 3H), 2.77 (m, 1H), 2.54 (q, 6.0 Hz,1H), 2.17-1.90 (m, 9H), 1.76 (m, 3H), 1.62-1.39 (m, 12H), 1.14 (d, 6.3Hz, 3H).

Example 32-[2-Methyl-4-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester

The title compound was prepared in a manner substantially the same asExample 1 to obtain the title compound as a semi-solid.

LC, R_(T)=2.56 mins; MS: 497.

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 6.96 (m, 1H), 6.39 (m, 2H), 4.04 (m,2H), 3.59 (t, 6.6 Hz, 2H), 3.45-3.17 (m, 5H), 3.02 (m, 3H), 2.79 (m,1H), 2.54 (q, 6.0 Hz, 1H), 2.30-1.90 (m, 9H), 1.76 (m, 3H), 1.62-1.39(m, 12H), 1.14 (d, 6.3 Hz, 3H).

Example 42-[2-Methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester

The title compound was prepared in a manner substantially the same asExample 1 to obtain the title compound as a semi-solid.

LC, R_(T)=2.61 mins; MS: 497.

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 6.96 (m, 1H), 6.39 (m, 2H), 4.04 (m,2H), 3.59 (t, 6.6 Hz, 2H), 3.50 (t, 7.2 Hz, 1H), 3.37 (dt, 2.2 Hz, 9.3Hz, 1H), 3.245 (m, 3H), 3.04 (m, 3H), 2.77 (m, 1H), 2.54 (q, 6.0 Hz,1H), 2.17-1.90 (m, 9H), 1.76 (m, 3H), 1.62-1.39 (m, 12H), 1.14 (d, 6.3Hz, 3H).

Example 52-[2-Methyl-4-(2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester

The title compound was prepared in a manner substantially the same asExample 1 to obtain the title compound as a semi-solid.

LC, R_(T)=2.62 mins; MS: 497.

¹H NMR (CDCl₃, 300 MHz), δ (ppm): Two sets of spectra were observed.

Example 62-[2-Methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one

2-[2-Methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester (150 mg) was treated with 1 mL (excess) of 4M HClin dioxane at 0° C. The stirring was continued at rt for 1 h. Thesolvent was evaporated and the solid was further dried under high vacuumat rt for 2 h to obtain the title compound as a tan solid.

LC, R_(T)=1.41 mins; MS: 397.

Example 72-[2-Methyl-4-((2R,3′R)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-oneHydrochloride

The title compound was prepared in a manner substantially the same asExample 1.

LC, R_(T)=1.38 mins; MS: 397.

Example 82-[2-Methyl-4-((2R,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-oneHydrochloride

The title compound was prepared in a manner substantially the same asExample 1

LC, R_(T)=1.4 mins; MS: 397.

Example 92-[2-Methyl-4-((2S,3′R)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-oneHydrochloride

The title compound was prepared in a manner substantially the same asExample 1.

LC, R_(T)=1.35 mins; MS: 397.

Example 108-Cyclopentylmethyl-2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one

To2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one(40 mg, 0.1 mmol) was added a solution of cyclopentane-carboxaldehyde(CAS 872-53-7, MW 98.14) (30 mg, 0.3 mmol) in 5 mL, followed by powdersodium triacetoxyborohydride under N₂ at r.t. The yellowish milkysuspension was stirred at r.t. overnight. The reaction was quenched withDCM (5 mL), NaHCO3 aq. (2 mL) and NaOH (1N, 1 mL). The two layers wereseparated, and the aqueous layer was extracted with DCM (5 mL). Thecombined DCM extracts were washed with sodium bicarbonate (5 mL), andbrine (5 mL), dried (anhydrous potassium carbonate), filtered, and thesolution was directly loaded onto a 10-g waters silica gel column,eluted with DCM, followed by 5% of 7N NH₃/MeOH in DCM. The collection ofthe fractions was evaporated to obtain a solid.

LC, R_(T)=1.65 mins; MS: 479.

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 6.96 (m, 1H), 6.39 (m, 2H), 3.55 (t,7.2 Hz, 2H), 3.45-3.17 (m, 5H), 3.44-3.19 (m, 3H), 2.53 (q, 8.1 Hz, 1H),2.25 (m, 3H), 2.07-1.91 (m, 8H), 1.74 (m, 4H), 1.62-1.41 (m, 12H), 1.20(m, 2H), 1.14 (d, 6.3 Hz, 3H).

Example 118-Cyclopentylmethyl-2-[2-methyl-4-((2R,3′R)-2-methyl-[1,3]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC, R_(T)=1.68 mins; MS: 479.

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 6.96 (m, 1H), 6.39 (m, 2H), 2.55 (t,7.2 Hz, 2H), 3.50 (t, 7.2 Hz, 1H), 3.45-3.10 (m, 4H), 3.01 (m, 1H), 2.89(m, bs, 1H), 2.78 (sextet, 6.9 Hz, 1H), 2.50 (q, 8.4 Hz, 1H), 2.27 (m,3H), 2.07-1.91 (m, 8H), 1.74 (m, 4H), 1.62-1.41 (m, 12H), 1.20 (m, 2H),1.13 (d, 6.3 Hz, 3H).

Example 128-Cyclopentylmethyl-2-[2-methyl-4-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC, R_(T)=1.7 mins; MS: 479.

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 6.96 (m, 1H), 6.39 (m, 2H), 3.55 (t,7.2 Hz, 2H), 3.45-3.17 (m, 5H), 3.44-3.19 (m, 3H), 2.53 (q, 8.1 Hz, 1H),2.25 (m, 3H), 2.07-1.91 (m, 8H), 1.74 (m, 4H), 1.62-1.41 (m, 12H), 1.20(m, 2H), 1.14 (d, 6.3 Hz, 3H).

Example 138-Cyclopentylmethyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC, R_(T)=1.67 mins; MS: 479.

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 6.96 (m, 1H), 6.39 (m, 2H), 2.55 (t,7.2 Hz, 2H), 3.50 (t, 7.2 Hz, 1H), 3.45-3.10 (m, 4H), 3.01 (m, 1H), 2.89(m, bs, 1H), 2.78 (sextet, 6.9 Hz, 1H), 2.50 (q, 8.4 Hz, 1H), 2.27 (m,3H), 2.07-1.91 (m, 8H), 1.74 (m, 4H), 1.62-1.41 (m, 12H), 1.20 (m, 2H),1.13 (d, 6.3 Hz, 3H).

Example 148-Cyclopentylmethyl-2-[2-methyl-4-(2-methyl-[1,3]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC, R_(T)=1.63 mins; MS: 479.

¹H NMR (CDCl₃, 300 MHz), δ (ppm): two sets of spectra were observed. Itis ambiguous to assign the spectra.

Example 152-[2-Methyl-4-((2R,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one

To a solution of acid chloride in DCM was added2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one(˜20 mg, 0.06 mmol) followed by potassium carbonate (40 mg, excess). Thecolorless suspension was allowed to stir under nitrogen overnight at rt.The reaction was quenched with DCM (5 mL) and aq. sodium bicarbonatesolution (2 mL). The two layers were separated. The aqueous layer wasextracted with DCM (5 mL). The combined DCM solution was dried overK₂CO₃, directly loaded onto a 10-g silica gel column, eluted with DCMand 5% 7N NH₃ solution of MeOH in DCM to get the product, as in thetable.

LC, R_(T)=2.52 mins; MS: 585.

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 7.49 (d, 8.4 Hz, 2H), 7.25 (d, 8.4 Hz,2H), 6.95 (m, 1H), 6.39 (m, 2H), 3.62 (m, 2H), 3.45-3.21 (m, 5H), 2.99(m, 1H), 2.80 (m, 1H), 2.54 (q, 8.4 Hz, 1H), 2.24 (m, 1H), 2.19-1.91 (m,8H), 1.87-1.39 (m, 10H), 1.15 (d, 6.3 Hz, 3H).

Example 162-[2-Methyl-4-((2R,3′R)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 15.

LC, R_(T)=2.62 mins; MS: 585.

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 7.49 (d, 8.4 Hz, 2H), 7.25 (d, 8.4 Hz,2H), 6.95 (m, 1H), 6.39 (m, 2H), 3.62 (m, 2H), 3.51 (t, 7.2 Hz, 1H),3.42-3.20 (m, 4H), 3.02 (m, 1H), 2.78 (m, 1H), 2.54 (q, 8.4 Hz, 1H),2.24-1.92 (m, 9H), 1.87-1.39 (m, 10H), 1.14 (d, 6.3 Hz, 3H).

Example 172-[2-Methyl-4-((2S,3′R)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 15.

LC, R_(T)=2.62 mins; MS: 585.

¹H NMR (CDCl₃, 300 MHz), δ (ppm): 7.49 (d, 8.4 Hz, 2H), 7.25 (d, 8.4 Hz,2H), 6.95 (m, 1H), 6.39 (m, 2H), 3.62 (m, 2H), 3.45-3.21 (m, 5H), 2.99(m, 1H), 2.80 (m, 1H), 2.54 (q, 8.4 Hz, 1H), 2.24 (m, 1H), 2.19-1.91 (m,8H), 1.87-1.39 (m, 10H), 1.15 (d, 6.3 Hz, 3H).

Example 182-[2-Methyl-4-(2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 15.

LC, R_(T)=2.62 mins; MS: 585.

¹H NMR (CDCl₃, 300 MHz), δ (ppm): two sets of spectra were observed. Itis ambiguous to assign the spectra.

Example 192-[2-Methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 15.

LC R_(T)=2.55 min, MS: 585 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.49 (d, 8.4 Hz, 2H), 7.25 (d, 8.4 Hz,2H), 6.95 (m, 1H), 6.39 (m, 2H), 3.62 (m, 2H), 3.51 (t, 7.2 Hz, 1H),3.42-3.20 (m, 4H), 3.02 (m, 1H), 2.78 (m, 1H), 2.54 (q, 8.4 Hz, 1H),2.24-1.92 (m, 9H), 1.87-1.39 (m, 10H), 1.14 (d, 6.3 Hz, 3H).

Example 202-[2-Methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylicacid tert-butyl ester

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=4.88 min, MS: 511 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 6.92 (d, 1H), 6.39-6.37 (m, 2H),3.81-3.73 (m, 2H), 3.59-3.40 (m, 2H), 3.36-3.20 (m, 7H), 3.01-2.9 (m,1H), 2.79-2.76 (m, 1H), 2.52 (q, 1H), 2.17-2.13 (m, 2H), 2.10 (s, 3H),2.04-1.51 (m, 13H), 1.45 (s, 9H), 1.13 (d, 3H).

Example 212-[4-((2S,3′S)-2-Methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylicacid tert-butyl ester

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=4.68 min, MS: 497 (M+H).

¹H NMR (300 MHz, CDCl3) δ (ppm): 7.01 (d, 2H), 6.52 (d, 2H), 3.83-3.75(m, 2H), 3.58 (t, 2H), 3.50 (t, 1H), 3.38-3.19 (m, 7H), 3.04-2.98 (m,1H), 2.79-2.75 (m, 1H), 2.53 (q, 1H), 2.19-2.10 (m, 4H), 2.03-1.71 (m,7H), 1.52-1.47 (m, 2H), 1.45 (s, 9H), 1.13 (d, 3H)

Example 224-{[2-Fluoro-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-methyl-carbamoyl}-4-propyl-piperidine-1-carboxylicacid tert-butyl ester

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=4.9 min, MS: 515 (M+H).

¹H NMR (300 MHz, CDCl3) δ (ppm): 6.98 (t, 1H), 6.30-6.23 (m, 2H),3.79-3.72 (m, 2H), 3.54 (t, 2H), 3.47 (t, 1H), 3.36-3.19 (m, 7H), 3.00(dt, 1H), 2.77 (q, 1H), 2.51 (q, 1H), 2.17-2.09 (m, 4H), 2.03-1.75 (m,7H), 1.52-1.46 (m, 2H), 1.45 (s, 9H), 1.12 (d, 3H).

Example 233-[2-Methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-oneHydrochloride

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=1.72 min, MS: 411 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.01 (d, 1H), 6.63-6.60 (m, 2H), 4.16(t, 1H), 3.81-3.21 (m, 17H), 3.31 (s, 3H), 2.60-2.45 (m, 1H), 2.38-2.28(m, 2H), 2.16-2.01 (m, 5H), 1.86-1.77 (m, 3H), 1.50 (d, 3H).

Example 243-[4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-oneHydrochloride

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=1.59 min, MS: 397 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.09 (d, 2H), 6.74 (d, 2H), 4.16 (t,1H), 3.81-3.19 (m, 17H), 2.60-2.47 (m, 1H), 2.38-2.27 (m, 2H), 2.15-1.97(m, 5H), 1.84-1.76 (m, 3H), 1.50 (d, 3H).

Example 253-[2-Fluoro-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-oneHydrochloride

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=1.74 min, MS: 415 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.13 (t, 1H), 6.53-6.49 (m, 2H), 4.21(t, 1H), 3.76-3.21 (m, 17H), 2.57-2.50 (m, 1H), 2.36-2.26 (m, 2H),2.12-1.97 (m, 5H), 1.84-1.77 (m, 3H), 1.50 (d, 3H).

Example 263-[2-Methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-9-(pyridine-4-carbonyl)-2,9-diaza-spiro[5.5]undecan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.42 min, MS: 516 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 8.67-8.63 (m, 2H), 7.77-7.73 (m, 1H),7.34 (dd, 1H), 6.93-6.91 (m, 1H), 6.40-6.38 (m, 2H), 4.20-3.88 (m, 4H),3.60-3.21 (m, 7H), 3.05-3.02 (m, 1H), 2.81 (q, 1H), 2.55 (q, 1H),2.13-1.46 (m, 17H), 1.15 (d, 3H).

Example 279-(Furan-3-carbonyl)-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.65 min, MS: 505 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.68 (s, 1H), 7.40 (t, 1H), 6.92 (d,1H), 6.55 (s, 1H), 6.40-6.38 (m, 2H) 4.05-3.91 (m, 2H), 3.64-3.56 (m,4H), 3.42-3.30 (m, 2H), 3.27-3.21 (m, 2H), 3.02 (dt, 1H), 2.79 (q, 1H),2.53 (q, 1H), 2.10 (s, 3H), 2.17-1.74 (m, 10H), 1.62-1.48 (m, 4H), 1.13(d, 3H).

Example 289-Benzoyl-2-[4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.67 min, MS: 501 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.31 (m, 5H), 7.22 (d, 2H), 6.94 (d,2H), 4.00-3.90 (m, 1H), 3.68 (m, 2H), 3.50-3.15 (m, 9H), 2.96 (q, 1H),2.65 (q, 1H), 2.10-1.67 (m, 11H), 1.59-1.54 (m, 2H), 1.37-1.23 (m, 1H),1.17 (d, 3H).

Example 299-(4-Fluoro-benzoyl-2-[4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.74 min, MS: 519 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.34 (dt, 2H), 7.00 (t, 2H), 6.94 (d,2H), 6.45 (d, 2H), 4.01-3.90 (m, 1H), 3.80-3.61 (m, 2H), 3.52 (t, 2H),3.43 (t, 1H), 3.33-3.15 (m, 5H), 2.94 (dt, 1H), 2.72 (q, 1H), 2.46 (q,1H), 2.10-1.37 (m, 14H), 1.06 (d, 3H).

Example 309-Cyclohexanecarbonyl-2-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.97 min, MS: 525 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 6.92 (t, 1H), 6.22-6.18 (m, 2H),3.84-3.70 (m, 2H), 3.49-3.18 (m, 10H), 3.91 (q, 1H), 2.62 (q, 1H),2.50-2.33 (m, 1H), 2.15-1.18 (m, 24H), 1.12 (d, 3H).

Example 312-[2-Fluoro-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-9-(tetrahydro-pyran-4-carbonyl)-2,9-diaza-spiro[5.5]undecan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.45 min, MS: 527 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 6.93 (t, 1H), 6.24-6.18 (m, 2H),3.95-3.75 (m, 6H), 3.48-3.30 (m, 10H), 3.19-3.13 (m, 2H), 3.04 (q, 1H),2.74-2.67 (m, 2H), 2.40-2.32 (m, 1H), 2.13-1.43 (m, 15H), 1.17 (d, 3H).

Example 329-Isopropyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=1.77 min, MS: 453 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 6.91 (d, 1H), 6.39-6.36 (m, 2H),3.53-3.48 (m, 2H), 3.38-3.18*m, 5H), 2.99 (dt, 1H), 2.86-2.69 (m, 4H),2.55-2.44 (m, 4H), 2.27-2.14 (m, 2H), 2.10 (s, 3H), 2.03-1.52 (m, 11H),1.12 (d, 3H), 1.05 (d, 6H).

Example 339-Cyclohexylmethyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.29 min, MS: 507 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 6.91 (d, 1H), 6.38-6.36 (m, 2H),3.54-3.48 (m, 2H), 3.39-3.18 (m, 5H), 2.99 (dt, 1H), 2.77-2.66 (m, 4H),2.51 (q, 1H), 2.23 (d, 2H), 2.13 (d, 2H), 2.09 (s, 3H), 2.03-1.43 (m,17H), 1.24-1.16 (m, 4H), 1.12 (d, 3H), 0.91-0.83 (m, 3H).

Example 349-Cyclopropylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=3.33 min, MS: 451 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 6.93 (d, 2H), 6.43 (d, 2H), 3.48 (t,2H), 3.41 (t, 1H), 3.29-3.12 (m, 4H), 2.91 (dt, 1H), 2.82-2.77 (m, 2H),2.69-2.67 (m, 2H), 2.43 (q, 1H), 2.35-2.31 (m, 1H), 2.20 (d, 2H),2.17-1.48 (m, 14H), 1.04 (d, 3H), 0.84-0.73 (m, 1H), 0.42 (m, 2H), 0.01(m, 2H).

Example 352-[4-((2S,3′S)-2-Methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-9-(tetrahydro-pyran-4-yl)-2,9-diaza-spiro[5.5]undecan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=3.24 min, MS: 481 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.01 (d, 2H), 6.51 (d, 2H), 4.00 (dd,2H), 3.56 (t, 2H), 3.49 (t, 1H), 3.40-3.20 (m, 7H), 2.99 (dt, 1H),2.99-2.83 (m, 2H), 2.76 (q, 1H), 2.53-2.44 (m, 5H), 2.28-1.54 (m, 16H),1.12 (d, 3H).

Example 369-Benzyl-2-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.14 min, MS: 505 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.37-7.24 (m, 5H), 7.00 (t, 1H),6.31-6.24 (m, 2H), 3.54-3.46 (m, 4H), 3.36-3.20 (m, 4H), 3.00 (dt, 1H),2.79-2.74 (m, 3H), 2.52 (q, 1H), 2.35-2.27 (m, 4H), 2.04-1.76 (m, 10H),1.60-1.54 (m, 3H), 1.13 (d, 3H).

Example 372-[2-Fluoro-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-9-furan-2-ylmethyl-2,9-diaza-spiro[5.5]undecan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2 min, MS: 495 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.37 (d, 1H), 6.98 (t, 1H), 6.31-6.23(m, 3H), 6.18 (d, 1H), 3.56-3.44 (m, 5H), 3.35-3.18 (m, 4H), 2.99 (dt,1H), 2.78-2.72 (m, 3H), 2.53-2.42 (m, 3H), 2.30-2.24 (m, 2H), 2.19-2.05(m, 1H), 1.99-1.77 (m, 8H), 1.62-1.40 (m, 3H), 1.11 (d, 3H).

Example 382-{4-[4-(2S-2-Methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.61 min, MS: 497 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.49 (d, 2H), 6.94 (d, 2H), 4.04 (d,2H), 3.78-3.67 (m, 4H), 3.04 (t, 2H), 2.92 (dd, 2H), 2.83-2.50 (m, 4H),2.07 (t, 2H), 1.98-1.6 (m, 12H), 1.45 (s, 9H), 1.3 (d, 3H).

Example 392-{4-[4-(2S-2-Methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-trifluoromethyl-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.75 min, MS: 565 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.16 (d, 1H), 7.04 (2, H), 3.96 (d,2H), 3.74 (d, 2H), 3.60 (d, 2H), 3.12-3.01 (m, 4H), 2.87 (m, 3H), 2.66(dd, 1H), 2.10 (t, 2H), 2.0-1.82 (m, 8H), 1.77-1.61 (m, 2H), 1.5 (d,2H), 1.4 (s, 9H), 1.1 (d, 3H).

Example 402-{4-[4-(2S-2-Methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-fluoro-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.71 min, MS: 516 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.17 (t, 1H), 6.65 (dd, 2H), 3.99 (d,2H) 3.68 (m, 4H), 3.09 (t, 2H), 2.95 (d, 2H), 2.74 (m, 4H), 2.09 (t,2H), 1.99-1.62 (m, 10H), 1.54-1.41 (m, 11H), 1.09 (d, 3H).

Example 412-{4-[34(2S,3′S)-2-Methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.74 min, MS: 497 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.37 (d, 2H), 6.47 (d, 2H), 3.93 (d,2H), 3.66 (t, 2H), 3.52 (t, 1H), 3.43-3.30 (m, 2H), 3.19 (dd, 2H), 2.96(t, 1H), 2.79 (m, 1H), 2.62 (m, 1H), 2.31 (m, 1H), 2.01-1.82 (m, 7H),1.67 (m, 1H), 1.58 (d, 2H), 1.50-1.30 (m, 13H), 1.10 (d, 3H).

Example 422-{4-[3-((2S,3′S)-2-Methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.97 min, MS: 565 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.05 (d, 1H), 6.76 (d, 1H), 6.63 (dd,1H), 3.98 (d, 2H), 3.66-3.40 (m, 5H), 3.32 (t, 1H), 3.23 (dd, 1H), 3.11(t, 2H), 2.88 (m, 1H), 2.69 (m, 1H), 2.38 (m, 1H), 2.10-2.00 (m, 4H),1.98-1.94 (m, 2H), 1.78-1.70 (m, 1H), 1.60-1.40 (m, 13H), 1.08 9 d, 3H).

Example 432-{4-[3-((2S,3′S)-2-Methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-fluoro-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.66 min, MS: 515 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.14 (t, 1H), 6.26-6.23 (m, 2H), 3.99(d, 2H), 3.65 (t, 2H), 3.58 (dd, 1H), 3.49-3.34 (m, 2H), 3.30-3.04 (m,4H), 2.86 (m, 1H), 2.65 (m, 1H), 2.36 (m, 1H), 2.11-1.93 (m, 7H), 1.78(m, 1H), 1.65-1.43 (m, 15), 1.10 (d, 3H).

Example 442-{4-[4-(2S-2-Methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-oneHydrochloride

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.43 min, MS: 397 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.86 (d, 2H), 7.73 (d, 2H), 3.93-3.84(m 5H), 3.67 (m, 2H), 3.60-3.56 (m, 2H), 2.50-2.35 (m, 4H), 2.24 (t,2H), 2.13-2.09 (m, 4H), 1.88-1.80 (m, 4H), 1.53 (d, 3H).

Example 452-{4-[4-(2S-2-Methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-oneHydrochloride

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=1.89 min, MS: 465 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.57 (d, 2H), 7.44 (d, 1), 4.01 (d,2H), 3.83 (m, 1H), 3.73 (t, 2H), 3.61-3.50 (m, 4H), 3.25-3.20 (m, 4H),2.33-2.25 (m, 5H), 2.12-2.08 (m, 5H), 1.93-1.75 (m, 4H), 1.50 (d, 3H).

Example 462-{4-[4-(2S-2-Methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-fluoro-phenyl}-2,8-diaza-spiro[4.5]decan-1-oneHydrochloride

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=3.19 min, MS: 415 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.34 (t, 1H), 7.06 (dd, 2H), 3.91 (d,2H), 3.86-3.80 (m, 1H), 3.75 (t, 2H), 3.60-3.49 (m, 5H), 3.26-3.21 (m,2H), 3.18-3.10 (m, 2H), 2.35-2.23 (m, 4H), 2.18-1.78 (m, 8H), 1.53 (d,3H).

Example 472-{4-[3-((2S,3′S)-2-Methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-oneHydrochloride

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.56 min, MS: 397 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.42 (dd, 2H), 6.72 (t, 2H), 3.84 (m,3H), 3.61-3.49 (m, 6H), 3.24-3.19 (m, 3H), 2.47 (dd, 1H), 2.20 (t, 3H),2.18-2.07 (m, 3H), 1.95-1.88 (m, 6H), 1.79-1.68 (m, 3H), 1.47 (t, 3H).

Example 48 2-{4-[3-((2S,3′S)-2-Methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-oneHydrochloride

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.9 min, MS: 465 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.27 (dd, 1H), 6.94 (d, 2H), 3.75-2.68(m, 3H), 3.60-3.48 (m, 6H), 3.24-3.20 (m, 3H), 2.51 (dd, 1H), 2.25 (t,3H), 2.15-2.07 (m, 3H), 1.92-1.79 (m, 7H), 1.70-1.63 (m, 3H), 1.48 (t,3H).

Example 492-{4-[3-((2S,3′S)-2-Methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-fluoro-phenyl}-2,8-diaza-spiro[4.5]decan-1-oneHydrochloride

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.61 min, MS: 415 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.23-7.19 (m, 1H), 6.51 (t, 2H),3.76-3.70 (m, 3H), 3.61-3.51 (m, 6H), 3.25-3.21 (m, 3H), 2.48 (m, 1H),2.26-2.20 (m, 3H), 2.17-2.09 (m, 3H), 1.91-1.76 (m, 7H), 1.68-1.60 (m,3H), 1.47 (t, 3H).

Example 508-Benzenesulfonyl-2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=4.99 min, MS: 537 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.79 (d, 2H), 7.69-7.60 (m, 3H), 7.38(d, 2H), 7.01 (d, 2H), 3.85-3.80 (m, 3H), 3.74 (t, 1H), 3.68-3.64 (m,3H), 3.25-3.20 (m, 3H), 2.79 (t, 2H), 2.66 (t, 2H), 2.28-1.80 (m, 14H),1.65 (m, 1H), 1.47 (d, 3H).

Example 518-(4-Fluoro-benzoyl)-2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=4.59 min, MS: 519 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.52-7.44 (m, 4H), 7.21 (t, 2H), 7.03(d, 2H), 3.86-3.82 (m, 6H), 3.48-3.30 (m, 3H), 3.2 (m, 3H), 2.8 (t, 2H),2.35-1.98 (m, 8H), 1.90-1.77 (m, 6H), 1.45 (d, 3H).

Example 528-Cyclohexanecarbonyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=4.96 min, MS: 525 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.20 (t, 1H), 6.81 (d, 2H), 4.35-4.30(m, 1H), 4.05-4.00 (m, 1H), 3.94-3.86 (m, 4H), 3.73 (t, 3H), 3.51-3.42(m, 3H), 3.17-3.08 (m, 1H), 2.91-2.83 (m, 3H), 2.68 (m, 1H), 2.32-2.19(m, 5H), 2.11-2.04 (m, 4H), 1.89-160 (m, 13H) 1.44 (d, 3H).

Example 538-(4-Fluoro-benzenesulfonyl)-2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=5.3 min, MS: 555 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.88-7.84 (m, 2H), 7.42-7.33 (m, 4H),6.67 (d, 2H), 4.30-4.26 (m, 1H), 3.75 (t, 2H), 3.67-3.56 (m, 6H),3.38-3.33 (m, 2H), 2.69 (t, 2H), 2.48-2.32 (m, 4H), 2.06-1.78 (m, 8H),1.75 (m, 3H), 1.45 (d, 3H).

Example 542-{4-[3-((2S,3′S)-2-Methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-8-(tetrahydro-pyran-4-carbonyl)-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=4.26 min, MS: 509 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.39 (d, 2H), 6.67 (d, 2H), 4.39 (m,1H), 4.15 (m, 1H), 3.97 (m, 2H), 3.83 (t, 2H), 3.66. 3.47 (m, 7H),3.03-2.98 (m, 3H), 2.5-2.35 (m, 2H) 2.21 (t, 2H), 2.10-2.00 (m, 1H),1.88-1.79 (m, 10H), 1.65-1.60 (m, 6H), 1.45 (d, 3H).

Example 558-Cyclopentanecarbonyl-2-{4-[34(2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=5.24 min, MS: 561 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.21 (d, 1H), 6.93 (m, 2H), 4.38-4.28(m, 1H), 4.10-4.06 (m, 1H), 3.79-3.63 (m, 8H), 3.43-3.40 (m, 3H),2.50-2.50 (m, 2H), 2.25 (m, 2H), 2.07 (m, 2H), 1.88-1.64 (m, 15H), 1.47(d, 3H).

Example 568-Cyclopropylmethyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=1.92 min, MS: 469 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.22 (t, 1H), 6.85 (d, 2H), 3.94-3.82(m, 3H), 3.77-3.70 (t, 2H), 3.68-3.60 (m, 2H), 3.53-3.42 (m, 2H), 3.36(s, 2H), 3.27-3.19 (m, 2H), 3.02 (d, 2H), 2.91-2.83 (m, 2H), 2.32-1.79(m, 13H), 1.43 (d, 3H), 1.10-1.06 (m, 1H), 0.75 (s, 2H), 0.43 (d, 2H).

Example 578-Cyclopentylmethyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=3.91 min, MS: 497 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.21 (t, 1H), 6.82 (d, 2H), 3.86 (d,2H), 3.70 (t, 2H), 3.67-3.54 (m, 1H), 3.34 (s, 2H), 3.23 (m, 1H),3.18-3.09 (m, 4H), 2.88-2.78 (m, 2H), 2.57-2.39 (m, 4H), 2.20-1.45 (m,20H), 1.40-1.17 (m, 5H).

Example 588-Cyclohexylmethyl-2-{4-[34(2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=4.41 min, MS: 561 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.11 (d, 1H), 6.81 (m, 2H), 3.65-3.62(m, 3H), 3.60-3.46 (m, 2H), 3.35 (s, 2H), 3.25 (m, 1H), 2.92-2.84 (m,4H), 2.71 (m, 1H), 2.46 (m, 1H), 2.19-2.08 (m, 8H), 2.01-1.94 (m, 2H),1.82-1.45 (m, 13H), 1.35-1.24 (m, 2H), 1.15 (d, 3H), 0.93 (dd, 2H).

Example 592-{2-Fluoro-4-[34(2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-8-(tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=3.61 min, MS: 513 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.08 (t, 1H), 6.40-6.32 (m, 2H),3.95-3.90 (m, 2H), 3.68-3.58 (m, 3H), 3.51-3.34 (m, 4H), 3.33 (s, 2H),3.25 (m, 1H), 2.89 (d, 4H), 2.69 (m, 1H), 2.45 (m, 1H), 2.22-1.90 (m,11H), 1.89-1.40 (m, 8H), 1.38-1.20 (m, 2H), 1.15 (d, 3H).

Example 602-[4-((2S,3′S)-2-Methyl-[1,3]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-8-phenylacetyl-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=3.01 min, MS: 569 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.98-7.91 (m, 4H), 7.60-7.50 (m, 3H),7.17 (d, 1H), 6.82-6.80 (m, 2H), 4.48 (m, 1H), 3.81 (m, 1H), 3.67 (m,2H), 3.58 (t, 1H), 3.46-3.34 (m, 4H), 3.27-3.21 (m, 2H), 3.04-2.97 (m,1H), 2.92-2.82 (q, 2H), 2.65 (q, 1H), 2.25 (m, 2H), 2.10-1.95 (m, 3H),1.83-1.78 (m, 3H), 1.68-1.40 (m, 3H), 1.18 (d, 3H).

Example 618-(2-Methoxy-acetyl)-2-[4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=4.31 min, MS: 523 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.21 (d, 1H), 6.90 (d, 2H), 4.30 (m,1H), 4.21 (d, 2H), 4.05-3.97 (m, 1H), 3.93-3.75 (m, 2H), 3.69 (t, 2H),3.61-3.57 (m, 2H), 3.41 (s, 3H), 3.36-3.33 (m, 2H), 3.22-3.15 (m, 2H),2.53-2.45 (m, 1H), 2.27-2.24 (m, 5H), 2.10-2.04 (m, 2H), 1.95-1.65 (m,6H), 1.42 (d, 3H).

Example 622-[4-((2S,3′S)-2-Methyl-[1,3]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-8-(naphthalene-2-carbonyl)-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=3.21 min, MS: 605 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.98-7.91 (m, 4H), 7.60-7.50 (m, 3H),7.17 (d, 1H), 6.82-6.80 (m, 2H), 4.48 (m, 1H), 3.81 (m, 1H), 3.67 (m,2H), 3.58 (t, 1H), 3.46-3.34 (m, 4H), 3.27-3.21 (m, 2H), 3.04-2.97 (m,1H), 2.92-2.82 (q, 2H), 2.65 (q, 1H), 2.25 (m, 2H), 2.10-1.95 (m, 3H),1.83-1.78 (m, 3H), 1.68-1.40 (m, 3H), 1.18 (d, 3H).

Example 638-Benzoyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.93 min, MS: 555 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.49-7.44 (m, 5H), 7.21 (d, 2), 6.93(m, 2H), 4.42 (m, 1H), 4.16-4.11 (m, 1H), 3.83-3.54 (m, 6H), 3.38-3.34(m, 2H), 3.24-3.20 (m, 2H), 2.60-2.53 (m, 2H), 2.36-2.22 (m, 5H),2.15-2.10 (m, 3H), 1.97-1.78 (m, 4H), 1.47 (d, 3H).

Example 648-(Furan-3-carbonyl)-2-[4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.75 min, MS: 545 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.88 (s, 1H), 7.60 (s, 1H), 7.21 (d,1H), 6.87 (s, 2H), 6.64 (s, 1H), 4.38-4.06 (m, 2H), 3.82-3.66 (m, 4H),3.58-3.52 (m, 1H), 3.43-3.33 (m, 5H), 3.01-2.92 (q, 1H), 2.39-2.28 (m,1H), 2.26-2.05 (m, 5H), 1.99-1.80 (m, 4H), 1.74-1.60 (m, 3H), 1.35 (d,3H).

Example 658-(4-Methoxy-benzenesulfonyl)-2-[4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=3.19 min, MS: 621 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.74 (d, 2H), 7.18-7.04 (m, 3H), 6.89(m, 2H), 4.02 (m, 1H), 3.88 (s, 3H), 3.78-3.72 (m, 1H), 3.63-3.55 (m,8H), 3.23 (m, 2H), 2.75-2.68 (m, 2H), 2.54-2.48 (m, 1H), 2.35-2.29 (m,2H), 2.10-1.95 (m, 6H), 1.80-1.65 (m, 3H), 1.45 (d, 3H).

Example 668-Furan-2-ylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=2.22 min, MS: 531 (M+H).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.56 (s, 1H), 7.23 (d, 1H), 6.93 (d,2H), 6.50 (s, 1H), 6.44 (s, 1H), 4.09-4.07 (m, 1H), 3.95-3.93 (s, 2H),3.81-3.49 (m, 8H), 3.19-3.15 (m, 2H), 2.74-2.68 (m 2H), 2.54-2.49 (m,2H), 2.36-2.17 (m, 4H), 2.15-2.07 (m, 4H), 1.82-1.74 (m, 3H), 1.47 (d,3H).

Example 678-Cyclopropylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=3.72 min, MS: 505 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.29 (d, 1H), 6.94 (d, 2H), 4.15-4.10(m, 1H), 3.80-3.53 (m, 8H), 3.40-3.33 (m, 2H), 3.04 (d, 2H), 2.55 (m,2H), 2.39-2.17 (m, 6H), 2.13 (t, 1H), 2.08-2.00 (m, 3H), 1.83-1.76 (m,1H), 1.47 (d, 3H), 1.2-1.15 (m, 1H), 0.79 (d, 2H), 0.49 (d, 2H).

Example 682-[4-((2S,3′S)-2-Methyl-[1,3]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-8-(tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=3.68 min, MS: 549 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.29 (d, 1H), 6.96 (d, 2H), 4.17 (m,2H), 3.97-3.93 (d, 4H), 3.85-3.77 (m, 2H), 3.72-3.32 (m, 8H), 3.25-3.22(m, 2H), 3.03 (d, 2H), 2.59-2.53 (m, 1), 2.38-2.11 (m, 8H), 2.08-1.95(m, 2H), 1.83-1.74 (m, 4H), 1.44 (d, 3H), 1.44-1.35 (m, 2H).

Example 692-[4-((2S,3′S)-2-Methyl-[1,3]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-oneHydrochloride

The title compound was prepared in a manner substantially the same asExample 1.

LC R_(T)=3.4 min, MS: 451 (M+H).

¹H NMR (300 MHz, CD₃OD) δ (ppm): 7.6 (d, 1H), 6.95 (m, 2H), 4.24-4.21(m, 1H), 3.86-3.80 (m, 1H), 3.75-3.67 (m, 3H), 3.56-3.48 (m, 3H),3.40-3.34 (m, 2H), 3.26-3.21 (m, 2H), 2.63-2.57 (m, 1H), 2.42-2.23 (m,5H), 2.15-2.08 (m, 4H), 1.91-1.81 (m, 4H), 1.52 (d, 3H).

Biological Examples Example 70

This Example 70 demonstrates the efficacy of the compounds of thisinvention as H3 receptor ligands. The compounds of this invention havebeen demonstrated to displace [³H]-methylhistamine radioligand bindingto mammalian cell membranes expressing rhesus (Macacca Mulatta) H3receptor. These compounds display rhesus H3 affinity constants (Ki) inthe range of 1 μM to <1 nM. Additionally, the compounds of thisinvention have been demonstrated by GTPγS radioligand binding assay toinhibit rhesus H3 constitutive functional activity in cell membranes.This inhibition of basal rhesus H3-mediated GTPγS radioligand bindingdemonstrates that the compounds of this invention find utility asinverse agonists. These compounds decreased rhesus H3 GTPγS radioligandbinding by 0-40% below basal levels.

Rhesus H3 membranes were prepared from the Flp-In T-REx 293 Cell Line(Invitrogen) stably transfected with pcDNA5/FRT/TO (Invitrogen)containing the rhesus monkey (Macacca Mulatta) 445 amino acid H3receptor. (Genbank #AY231164). Stably transfected cultures wereamplified in tissue culture flasks by standard tissue culture methodsand induced to express rhesus H3 by exposure to 500 ng/ml tetracycline(Cellgro) for 24 hours. After induction, cells were dissociated fromflasks utilizing Cell Stripper (Cellgro). Cells were centrifuged (1K×g,5 min) and pellet frozen in an ethanol-dry ice bath to disrupt cellmembranes. Frozen cell pellet was re-suspended in 5 mM HEPES (pH 7.4,Invitrogen) at 10 ml/1000 cm2 of harvested cells. The cell suspensionwas drawn through an 18 gauge needle (2-3×) followed by a 23 gaugeneedle (2-3×) to further disrupt cell membranes. The cell suspension wascentrifuged (40K×g, 30 min). Cell membrane pellet was re-suspended in 5mM HEPES (pH 7.4, Invitrogen) at a final protein concentration of 10mg/ml. Rhesus H3 membranes were stored under liquid nitrogen prior touse in [3H]-Methylhistamine and GTP S radioligand binding assays.

Rhesus H3 radioligand binding assay was performed using rhesus H3receptor membranes (prepared as described above), [3H]-Methylhistamine(Perkin Elmer) and WGA SPA beads (wheat germ agglutinin scintillationproximity assay) beads (Amersham). The assay was performed in 96-wellOpti-Plates (Packard). Each reaction contained 50 μl rhesus H3 membranes(20-30 μg total protein), 50 μl WGA SPA beads (0.1 μg) and 50 μl of83Ci/mmol [³H]-Methylhistamine (final concentration 2 nM) and 50 μl oftested compound. The compounds of this invention and/or vehicle werediluted with binding buffer from 10 mM DMSO stocks. Assay plates weresealed with TopSeal (Perkin Elmer) and mixed on shaker (25° C., 1 hour).Assay plates were read on TopCount scintillation counter (Packard).Results were analyzed by Hill transformation and Ki values weredetermined by Cheng-Prusoff equation. The observed binding data for afew of the representative compounds of this invention are summarized inTable 1.

TABLE 1 Inverse Agonism: % inhibition of Basal Example Rhesus H3 GTPγSbinding in No. binding ki (nM) Rhesus H3 1 132 −24 2 248 −30 3 7 −23 443 −31 5 18 −13 6 11 −22 7 15 −22 8 0.8 −26 9 0.6 −35 10 12 −26 11 22−29 12 0.8 −20 13 0.8 −37 14 5.6 −31 15 118 −14 16 100 −13 17 1.4 −9 186.2 −10 19 1.4 −19 20 6.8 −18 21 7.3 −28 22 0.03 −27 23 0.07 −19 24 0.1−13 25 0.06 −22 26 4 −17 27 1.6 −19 28 0.5 −15 29 0.4 −17 30 0.7 −22 310.4 −19 32 0.4 −14 33 0.2 −14 34 0.2 −16 35 0.04 −18 36 0.06 −13 37 0.1−17 38 0.008 −25 39 0.9 −22 40 0.3 −21 41 5.6 −14 42 64 −15 43 4.3 −1944 0.1 −19 45 0.15 −19 46 0.1 −24 47 0.4 −17 48 0.6 −24 49 0.5 −22 500.24 −23 51 0.08 −17 52 0.2 −24 53 1.9 −13 54 3.3 −24 55 2.1 −27 56 0.04−23 57 0.1 −21 58 0.15 −19 59 4.6 −19 60 144 −19 61 193 −7 62 8.1 −19 6364 −18 64 9.6 −19 65 10.6 −18 66 5.5 −19 67 1.4 −12 68 4.2 −19 69 0.09−28

Example 71

This Example illustrates the study of efficacy of the compounds of thisinvention in increasing the wakefulness in animal models.

Male Sprague Dawley rats (Charles River, France) weighing 250±10 g wereanaesthetized with ZOLETIL® 50 (60 mg/kg ip) and mounted in astereotaxic apparatus. Cortical electrodes (small stainless steel screwelectrodes of 0.9 mm in diameter) were screwed into the bone over thesensorimotor cortex (1.5 mm lateral to the median suture and 1.5 mmbehind the fronto-parietal suture), the visual cortex (1.5 mm lateral tothe median suture and 1.5 mm in front of the parieto-occipital suture)and over the cerebellum (reference electrode). Cortical electrodes wereattached to a connector (Winchester, 7-lead) and fixed with dentalcement to the cranium.

After three weeks of post-operative recovery, animals were placed inplexiglass cylinders (60 cm diameter) with free access to food andwater. The temperature of the room was kept constant (21±1° C.) andlights were on from 7 a.m. to 7 p.m. The rats were recorded from 10 a.m.to 4 p.m. during three consecutive days: control day (D1), drug day (D2)and post drug day (D3). Vehicle (D1 and D3) or drug (D2) wereadministered 15 min before the recording.

Activity in sensorimotor and visual cortices were recorded by comparisonwith the reference electrode placed over the cerebellar cortex. Threestages were differentiated:

-   -   wakefulness (W) characterized by low voltage fast        electrocortical (ECoG) activity;    -   NREM sleep (non rapid eye movement or slow wave sleep: SWS)        characterized by an increase in electrocortical activity;        development of high-amplitude slow waves with some bursts of        sleep spindles;    -   REM sleep (rapid eye movement or paradoxical sleep: PS)        characterized by hypersynchronization of the theta rhythm in the        visual area.

Analysis of the ECoG signal was performed automatically by means of acomputerized system discriminating between the various sleep phasesusing sequential spectral analysis of ten seconds periods (Deltamed'ssoftware “Coherence”).

The compounds of this invention were dissolved in 0.6% MTC tween andadministered by oral route (po). The volume of injection was 0.5 ml/100g of body weight.

Two types of analysis were used to quantify the effects of the compoundsof this invention on sleep-wakefulness variables: the one hour-periodand the six hour-period analysis.

The results are expressed in minutes (one hour-period analysis) or asthe percentage of the control values (100%). Statistical analysis of thedata was carried out using the Student's t test for paired values todetermine significant variations from control values.

Example 72 Stress-Induced Ultrasonic Vocalizations Test in Adult Rats

This Example illustrates the study of efficacy of the compounds of thisinvention as antidepressive agents in animal models.

The procedure used was adapted from the technique described by Van DerPoel A. M, Noach E. J. K, Miczek K. A (1989) Temporal patterning ofultrasonic distress calls in the adult rat: effects of morphine andbenzodiazepines. Psychopharmacology 97:147-8. Rats were placed for atraining session in a cage with a stainless steel grid floor (MEDAssociates, Inc., St. Albans, Vt.). Four electric shocks (0.8 mA, 3 s)were delivered every 7 s and ultrasonic vocalizations (UV, 22 KHz) weresubsequently recorded with the Ultravox system (Noldus, Wageningen, TheNetherlands) during 2 min. A modified ultrasound detector (Mini-3 batmodel) connected to a microphone was used to transform ultrasonic soundinto audible sound. The signal was then filtered and sent to a computerwhere the Ultravox software recorded each bout of UV that lasted morethan 10 ms. Rats were selected on the basis of their UV duration (>40 s)and subjected to the test, 4 h after training. For the test, rats wereplaced in the same cage as that used for training. One electric shock(0.8 mA, 3 s) was delivered and UV (duration and frequency) weresubsequently recorded with the Ultravox system during 2 min. Thecompounds of this invention were administered p.o. 60 min beforetesting.

Example 73 Forced-Swimming Test in Rats

This Example further illustrates the study of efficacy of the compoundsof this invention as antidepressive agents in animal models.

The procedure was a modification of that described by Porsolt et al.(1977) Depression: a new animal model sensitive to antidepressanttreatments. Nature 266:730-2. Rats were placed in individual glasscylinder (40 cm height, 17 cm diameter) containing water (21° C.) to aheight of 30 cm. Two swimming sessions were conducted (a 15-min trainingsession followed 24 h later by a 6-min test). After each swimmingsession, rats were placed under a heating lamp to avoid hypothermia. Theduration of immobility was measured during the 6-min test. The compoundsof this invention were administered p.o. twice (15 min after trainingsession and 60 min before the test).

Although the invention has been illustrated by certain of the precedingexamples, it is not to be construed as being limited thereby; butrather, the invention encompasses the generic area as hereinbeforedisclosed. Various modifications and embodiments can be made withoutdeparting from the spirit and scope thereof.

1. A compound of formula (I):

wherein m is 1 or 2; n is 1 or 2; p is 1 or 2; R₁ is hydrogen,(C₁-C₄)alkyl, CF₃, or (C₁-C₄)alkoxy-(C₁-C₄)alkyl; R₂ is hydrogen,halogen, (C₁-C₄)alkyl or CF₃; and R₃ is hydrogen, (C₁-C₄)alkyl,(C₁-C₆)alkyloxycarbonyl, (C₃-C₇)cycloalkyl(C₁-C₆)alkyl, substituted orunsubstituted heterocycle, substituted or unsubstitutedheterocycloalkyl(C₁-C₆)alkyl, substituted or unsubstituted 5- or6-membered ring heteroaryl(C₁-C₆)alkyl, substituted or unsubstitutedbenzyl, (C₁-C₄)alkoxymethylcarbonyl, substituted or unsubstituted(C₃-C₇)cycloalkanecarbonyl, substituted or unsubstituted benzylcarbonyl,substituted or unsubstituted (C₆-C₁₀)arylcarbonyl, substituted orunsubstituted 5 or 6-membered ring heteroarylcarbonyl, substituted orunsubstituted heterocyclecarbonyl, substituted or unsubstitutedbenzenesulfonyl, wherein the substituents are selected from halogen,trifluoromethoxy, (C₁-C₄)alkoxy, (C₁-C₄)alkyl and CF₃; or a salt,enantiomer or diastereomer thereof.
 2. The compound according to claim1, wherein n, p, and m are 1; R₁ is methyl, ethyl, isopropyl, n-propylor methoxymethyl; R₂ is hydrogen, fluorine, chlorine, methyl, ethyl orCF₃; and R₃ is hydrogen, methoxyethylcarbonyl, tert-butyloxycarbonyl,cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl,tetrahydropyranyl, benzyl, furanylmethyl, cyclopentane-carbonyl,cyclohexanecarbonyl, trifluoromethoxybenzoyl, fluorobenzoyl,benzyl-carbonyl, naphthylcarbonyl, benzenesulfonyl, fluorobenzenesulfonyl or methoxybenzenesulfonyl; or a salt, enantiomer ordiastereomer thereof.
 3. The compound according to claim 1, wherein n is2 and m is 1; or n is 1 and m is 2; p is 1 or 2; R₁ is methyl or ethyl;R₂ is hydrogen, fluorine, chlorine, methyl, ethyl or CF₃; and R₃ ishydrogen, isopropyl, tert-butyloxycarbonyl, cyclopropylmethyl,cyclopentylmethyl, cyclohexylmethyl, tetrahydropyranyl, benzyl,furanylmethyl, tetrahydropyranylmethyl, cyclopentane carbonyl,cyclohexane carbonyl, tetrahydropyran carbonyl, benzoyl,trifluoromethoxybenzoyl, fluorobenzoyl, benzyl carbonyl, naphthylcarbonyl, pyridine carbonyl or furan carbonyl; or a salt, enantiomer ordiastereomer thereof.
 4. The compound of claim 1 selected from the groupconsisting of:2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester;2-[2-methyl-4-((2R,3′R)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester;2-[2-methyl-4-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester;2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester;2-[2-methyl-4-(2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester;2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylicacid tert-butyl ester;2-[4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylicacid tert-butyl ester;4-{[2-fluoro-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-methyl-carbamoyl}-4-propyl-piperidine-1-carboxylicacid tert-butyl ester;2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl]-piperidin-1′-yl)-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester;2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-trifluoromethyl-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester;2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-fluoro-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester;2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester;2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester;2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-fluoro-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester;2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-t-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;8-cyclopentylmethyl-2-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;8-benzenesulfonyl-2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;8-(4-methoxy-benzenesulfonyl)-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;2-[2-methyl-4-((2R,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;2-[2-methyl-4-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;8-cyclopentylmethyl-2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;8-cyclopentylmethyl-2-[2-methyl-4-((2R,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;8-cyclopentylmethyl-2-[2-methyl-4-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;8-cyclopentylmethyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;2-[2-methyl-4-((2R,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;2-[2-methyl-4-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;2-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;3-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;3-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;3-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;3-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-9-(pyridine-4-carbonyl)-2,9-diaza-spiro[5.5]undecan-1-one;9-(furan-3-carbonyl)-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;9-benzoyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;9-(4-fluoro-benzoyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;9-cyclohexanecarbonyl-2-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;2-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-9-(tetrahydro-pyran-4-carbonyl)-2,9-diaza-spiro[5.5]undecan-1-one;9-isopropyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;9-cyclohexylmethyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;9-cyclopropylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-9-(tetrahydro-pyran-4-yl)-2,9-diaza-spiro[5.5]undecan-1-one;9-benzyl-2-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;2-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-9-furan-2-ylmethyl-2,9-diaza-spiro[5.5]undecan-1-one;2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-fluoro-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-fluoro-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;8-(4-fluoro-benzoyl)-2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;8-cyclohexanecarbonyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;8-(4-fluoro-benzenesulfonyl)-2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-8-(tetrahydro-pyran-4-carbonyl)-2,8-diaza-spiro[4.5]decan-1-one;8-cyclopentanecarbonyl-2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;8-cyclopropylmethyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;8-cyclopentylmethyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;8-cyclohexylmethyl-2-{4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;2-{2-fluoro-4-[3-((2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-8-(tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one;2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-8-phenylacetyl-2,8-diaza-spiro[4.5]decan-1-one;8-(2-methoxy-acetyl)-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-8-(naphthalene-2-carbonyl)-2,8-diaza-spiro[4.5]decan-1-one;8-benzoyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;8-(furan-3-carbonyl)-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;8-furan-2-ylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;8-cyclopropylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-8-(tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one;and2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;or a salt thereof.
 5. The compound of claim 1 selected from the groupconsisting of:8-cyclopentylmethyl-2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;8-cyclopentylmethyl-2-[2-methyl-4-((2R,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;8-cyclopentylmethyl-2-[2-methyl-4-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;8-cyclopentylmethyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;2-[2-methyl-4-((2R,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;2-[2-methyl-4-((2R,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;2-[2-methyl-4-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;2-[2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;3-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;3-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;3-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;9-isopropyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;9-cyclohexylmethyl-2-[2-methyl-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;9-cyclopropylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-9-(tetrahydro-pyran-4-yl)-2,9-diaza-spiro[5.5]undecan-1-one;9-benzyl-2-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;2-[2-fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-t-yl)-phenyl]-9-furan-2-ylmethyl-2,9-diaza-spiro[5.5]undecan-1-one;8-cyclopropylmethyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;8-cyclopentylmethyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;2-{2-fluoro-4-[34(2S,3′S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-8-(tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one;8-furan-2-ylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;8-cyclopropylmethyl-2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;and2-[4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenyl]-8-(tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one;or a salt thereof.
 6. The compound according or claim 1 which has theformula (II):

wherein R₁, R₂, R₃, m and n are as defined in claim
 1. 7. Apharmaceutical composition comprising one or more compound of claim 1 ora pharmaceutically acceptable salt, an enantiomer, or a diastereomerthereof in combination with one or more pharmaceutically acceptablecarriers, diluents or excipients.
 8. A pharmaceutical compositioncomprising one or more compound of claim 2 or a pharmaceuticallyacceptable salt, an enantiomer, or a diastereomer thereof in combinationwith one or more pharmaceutically acceptable carriers, diluents orexcipients.
 9. A pharmaceutical composition comprising one or morecompound of claim 3 or a pharmaceutically acceptable salt, anenantiomer, or a diastereomer thereof in combination with one or morepharmaceutically acceptable carriers, diluents or excipients.
 10. Apharmaceutical composition comprising one or more compound of claim 4 ora pharmaceutically acceptable salt thereof in combination with one ormore pharmaceutically acceptable carriers, diluents or excipients.
 11. Apharmaceutical composition comprising one or more compound of claim 5 ora pharmaceutically acceptable salt thereof in combination with one ormore pharmaceutically acceptable carriers, diluents or excipients.
 12. Amethod of treating a disease in a patient, said disease selected fromthe group consisting of a sleep disorder, dementia, Alzheimer's disease,multiple sclerosis, cognitive disorder, attention deficit hyperactivitydisorder and depression, comprising administering to said patient atherapeutically effective amount of a compound according to claim
 1. 13.The method according to claim 12, wherein the sleep disorder is selectedfrom the group consisting of narcolepsy, circadian rhythm sleepdisorder, obstructive sleep apnea, periodic limb movement and restlessleg syndrome, excessive sleepiness and drowsiness due to medicationside-effect.
 14. The method according to claim 12, wherein the sleepdisorder is narcolepsy.
 15. A method for treating a disease in apatient, said disease selected from the group consisting of cognitiveimpairment associated with schizophrenia (CIAS), an anxiety disorder,panic disorder and post-traumatic stress disorder, major depressivedisorder, dementia of Alzheimer type (DAT), cognitive deficits relatedto neurological diseases chosen from Alzheimer, Parkinson or Huntington,age related cognitive impairment, mild cognitive impairment, vasculardementia, Lewis Body dementia, cognition associated with cognitivedeficits, and obesity comprising administering to said patient atherapeutically effective amount of a compound according to claim
 1. 16.The method according to claim 15, wherein the disease is cognitiveimpairment associated with schizophrenia (CIAS).
 17. The methodaccording to claim 15, wherein the disease is dementia of Alzheimer type(DAT).